FR2466459A1 - Hypolipaemic and hypocholesterolaemic ester(s) - of phenoxy-isobutyric acid and N-hydroxy nicotinamide(s) - Google Patents

Hypolipaemic and hypocholesterolaemic ester(s) - of phenoxy-isobutyric acid and N-hydroxy nicotinamide(s) Download PDF

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FR2466459A1
FR2466459A1 FR7925279A FR7925279A FR2466459A1 FR 2466459 A1 FR2466459 A1 FR 2466459A1 FR 7925279 A FR7925279 A FR 7925279A FR 7925279 A FR7925279 A FR 7925279A FR 2466459 A1 FR2466459 A1 FR 2466459A1
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sep
phenoxy
hydroxymethylnicotinamide
preparation
chlorophenoxy
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FR2466459B1 (en
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Henri Cousse
Gilbert Mouzin
Jean-Pierre Rieu
Andre Delhon
Henri Lauressergues
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Pierre Fabre SA
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Pierre Fabre SA
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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
    • 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
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention concerne une classe d'esters de l'acide clofibrique, leur procédé de préparation, leurs applications thérapeutiques ainsi que les compositions pharmaceutiques en résultant. Ces esters répondent à la formule générale suivante : (CF DESSIN DANS BOPI) où n = 0 ou n = 1 ; R = halogène, halogéno benzoyl (CF DESSIN DANS BOPI) Ils seront notamment utilisés dans les différents types d'hyperlipidémies en vue de la prévention et du traitement de l'athérosclérose et de ses conséquences.The invention relates to a class of clofibric acid esters, their preparation process, their therapeutic applications as well as the pharmaceutical compositions resulting therefrom. These esters correspond to the following general formula: (CF DRAWING IN BOPI) where n = 0 or n = 1; R = halogen, halo benzoyl (CF DRAWING IN BOPI) They will be used in particular in the various types of hyperlipidemias with a view to the prevention and treatment of atherosclerosis and its consequences.

Description

La présente invention, réalisée au Centre de Recherches
Pierre FABRE, concerne une classe d'esters de l'acide clofibrique, leur procédé de préparation, leurs applications thérapeutiques ainsi que les compositions pharmaceutiques en résultant.The present invention, carried out at the Research Center
Pierre FABRE relates to a class of esters of clofibric acid, their process of preparation, their therapeutic applications as well as the pharmaceutical compositions resulting therefrom.

Comme rappelé dans le texte du brevet français nO 74.16962 du 15 mai 1974, au nom de la demanderesse, il est admis qu'un lien existe entre le risque de thrombose artérielle et la plupart des troubles du métabolisme lipidique. Pour corriger ces troubles, il est habituellement utilisé des médicaments contenant du clofibrate ou de l'acide nicotinique. As recalled in the text of the French patent No. 74.16962 of May 15, 1974, on behalf of the applicant, it is accepted that there is a link between the risk of arterial thrombosis and most disorders of lipid metabolism. To correct these disorders, it is usually used drugs containing clofibrate or nicotinic acid.

Cependant, ces deux composes actifs n'agissent pas exactement sur les mêmes facteurs et leur association est souvent nécessaire pour un traitement adéquat des troubles observés. However, these two active compounds do not act exactly on the same factors and their association is often necessary for an adequate treatment of the disorders observed.

Aussi, les composés chimiques, objet de l'invention décrite dans ce brevet nO 74.16962, et dérivés de l'acide phenoxy isobutyrique, ont permis de pallier cet inconvénient en possédant un spectre d'activité plus large. Also, the chemical compounds, object of the invention described in this patent No. 74.16962, and derivatives of phenoxy isobutyric acid, have overcome this disadvantage by having a broader spectrum of activity.

Ces composés répondent à la formule générale suivante

Figure img00010001

- A est un pont alcoyle inférieur de 2 à 6 atomes de carbone,
lineaire ou ramifié - X est un atome d'halogène ou un aryloxy - R = H ou alcoyle inférieur.These compounds correspond to the following general formula
Figure img00010001

- A is a lower alkyl bridge of 2 to 6 carbon atoms,
linear or branched - X is a halogen atom or aryloxy - R = H or lower alkyl.

Dans la demande de brevet français nO 77.13478 du 2 mai 1974, la demanderesse a également prouvé que les amides nicotiniques de formule

Figure img00010002

étaient de bons vecteurs des acides thérapeutiquement actifs.In the French patent application No. 77.13478 of May 2, 1974, the Applicant has also proved that the nicotinic amides of formula
Figure img00010002

were good vectors of therapeutically active acids.

La présente invention a pour objet les composés chimiques de formule générale suivante

Figure img00020001
The subject of the present invention is the chemical compounds of the following general formula
Figure img00020001

Par rapport aux brevets cités ci-dessus, la similitude chimique masque d'importantes différences métaboliques. Compared to the patents cited above, chemical similarity masks important metabolic differences.

En effet, les dérivés de l'invention libèrent, après hydrolyse par les estérases, une partie nicotonique de formule

Figure img00020002

n = 0 ou n = 1 qui est biologiquement dégradée pour conduire à la vitamine PP
Figure img00020003
Indeed, the derivatives of the invention release, after hydrolysis by esterases, a nicotonic part of formula
Figure img00020002

n = 0 or n = 1 which is biologically degraded to lead to vitamin PP
Figure img00020003

Afin de mieux faire ressortir l'originalité de l'invention, il est utile de preciser que les dérives antérieurement brevetés avec n > 2 ne permettent pas de conduire à la vitamine PP. In order to better highlight the originality of the invention, it is useful to specify that the derivatives previously patented with n> 2 do not lead to vitamin PP.

L'intérêt premier de cette nouvelle forme modulée de médicaments contenant les derivés de l'invention, notamment ceux où n = 1, est de libérer simultanément plusieurs composés actifs
- l'acide clofibrique lorsque R = Cl ;
- N-hydroxyméthyl nicotinamide qui se transforme vitamine
PP.The primary interest of this new modulated form of drugs containing the derivatives of the invention, especially those where n = 1, is to simultaneously release several active compounds
- clofibric acid when R = Cl;
- N-hydroxymethyl nicotinamide which turns vitamin
PP.

De même, lorsqu'on prend comme radical R

Figure img00020004

nous avons une liberation simultanee de :
- l'acide fénofibrique, plus couramment appelé procétofène ;
- et le N-hydroxyméthyl nicotinamide.Similarly, when one takes radical R
Figure img00020004

we have a simultaneous release of:
fenofibric acid, more commonly known as procetofen;
and N-hydroxymethyl nicotinamide.

L'action de ces différents metabolites est bien connue, notamment pour leur utilisation en thérapeutique, et on comprend l'avantage de l'invention puisque les preparations pharmaceutiques contenant les dérivés en cause ont une action par voie orale beaucoup plus importante que celle jouée par l'administration associée de ces métabolites. The action of these different metabolites is well known, particularly for their therapeutic use, and the advantage of the invention is understood since the pharmaceutical preparations containing the derivatives in question have a much greater oral action than that played by the associated administration of these metabolites.

L'invention a également pour objet un procedé d'obtention de ces nouveaux derivés.  The invention also relates to a process for obtaining these new derivatives.

Ces derivés d'hydroxynicotinamides ne sont pas synthétisables selon les brevets antérieurs auxquels nous nous sommes reférés.  These derivatives of hydroxynicotinamides are not synthesizable according to the prior patents we referred to.

En effet, selon le brevet nO 74.16962, les dérivés d'hydroxynicotinamides utilisés étaient obtenus selon le schéma suivant

Figure img00030001
Indeed, according to patent No. 74.16962, the hydroxynicotinamide derivatives used were obtained according to the following scheme
Figure img00030001

Dans le cas où n = 0, le N-hydroxynicotinamide est préparé par action de l'hydroxylamine sur le nicotinate d'éthyle, suivant la réaction suivante

Figure img00030002
In the case where n = 0, the N-hydroxynicotinamide is prepared by the action of hydroxylamine on ethyl nicotinate, according to the following reaction
Figure img00030002

Dans le cas ou n = 1, le N-hydroxymQthylnicotinamide est prépare par action du formol sur le nicotinamide suivant la réaction suivante

Figure img00030003
In the case where n = 1, N-hydroxymethylnicotinamide is prepared by the action of formaldehyde on nicotinamide following the following reaction.
Figure img00030003

Les procédes d'obtention des esters phenoxyisobutyriques sont décrits ci-après d'une manière détaillée. The processes for obtaining the phenoxyisobutyric esters are described below in detail.

I - Préparation du N-hydroxyméthyl nicotinamide
Dans un ballon de 250 ml, un mélange de 61,1 g (0,5 mole) de nicotinamide dans 65 ml de formol aqueux à 35 % (0,75 mole) dans 100 ml d'eau contenant 5 g de carbonate de potassium, est porte lentement au reflux pendant 2 heures.I - Preparation of N-hydroxymethyl nicotinamide
In a 250 ml flask, a mixture of 61.1 g (0.5 mole) of nicotinamide in 65 ml of 35% aqueous formalin (0.75 mole) in 100 ml of water containing 5 g of potassium carbonate. is slowly refluxed for 2 hours.

Après retour à température ambiante, le solvant réactionnel est évapore à siccite et le residu est recristallisé dans 570 ml d'alcool isopropylique. After returning to ambient temperature, the reaction solvent is evaporated to dryness and the residue is recrystallized from 570 ml of isopropyl alcohol.

On récupère, avec un rendement de 90 %, le produit de formule

Figure img00030004
The product of formula is recovered with a yield of 90%
Figure img00030004

Formule brute : C7H8N202
Masse moleculaire : 152,15
Cristaux blancs
Point de fusion : 1540C
Chromatographie sur plaque
- support : gel de silice 60 F 254 Merck
- solvant : chloroforme - méthanol - ammoniaque 80/18/2
- révélation : UV et iode
- Rf : 0,74
Spectre IR (KBr) : vNH 3 300 cm-, 3 lie 3 100 cm-,
VOH
VC=O amide 1 680 cm
Spectre RMN (DMSO d6/TMS) 6 (ppm)
4,85 (t, 2H, NH-I20H) ;
5,85 (t, 1H, NHCH20H) ; 7,65 (m, 1H, pyridine H5) ;
8.35 (m, 1H, pyridine H4) ; 8,8 (d.d, 1H, pyridine H6) ;
9,15 (d, 1H, pyridine H2) ; 9,4 (t, 1H, NHCH20H). Gross formula: C7H8N202
Molecular Weight: 152.15
White crystals
Melting point: 1540C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: chloroform - methanol - ammonia 80/18/2
- revelation: UV and iodine
- Rf: 0.74
IR spectrum (KBr): vNH 3300 cm -1, 3 dcm 3100 cm -1,
VOH
VC = O amide 1680 cm
NMR spectrum (DMSO d6 / TMS) 6 (ppm)
4.85 (t, 2H, NH-I20H);
5.85 (t, 1H, NHCH 2 OH); 7.65 (m, 1H, pyridine H5);
8.35 (m, 1H, pyridine H4); 8.8 (dd, 1H, pyridine H6);
9.15 (d, 1H, pyridine H2); 9.4 (t, 1H, NHCH 2 OH).

Solubilité : soluble dans l'eau bouillante, faiblement soluble
dans l'éthanol et le méthanol.Solubility: soluble in boiling water, slightly soluble
in ethanol and methanol.

II - Préparation du N-hydroxy nicotinamide
Dans un réacteur de 500 ml, on ajoute 10,2 g (0,44 atome/g) de sodium dans 200 ml de méthanol, puis on introduit dans la solution de méthylate 15,3 g (0,22 mole) de chlorhydrate d'hydroxylamine.II - Preparation of N-hydroxy nicotinamide
In a 500 ml reactor, 10.2 g (0.44 atom / g) of sodium in 200 ml of methanol are added, and then 15.3 g (0.22 mole) of hydrochloride are introduced into the methylate solution. hydroxylamine.

On porte 30 minutes au reflux, puis le mélange réactionnel est refroidi à 30 C et on introduit rapidement 27,5 ml (30,2 g) (0,2 mole) de nicotinate d'éthyle. The mixture is refluxed for 30 minutes, then the reaction mixture is cooled to 30 ° C. and 27.5 ml (30.2 g) (0.2 mol) of ethyl nicotinate are rapidly introduced.

On agite demi-heure à température ambiante, puis demi-heure au reflux. On concentre de moitié, puis on ajoute 150 ml d'eau ; le methanol résiduel est évaporé sous pression réduite. The mixture is stirred for half an hour at room temperature and then for half an hour under reflux. It is concentrated by half, then 150 ml of water are added; the residual methanol is evaporated under reduced pressure.

On refroidit la solution sur bain de glace et on amene à pH 5 avec une solution 4 N d'acide chlorhydrique. The solution is cooled on an ice bath and brought to pH 5 with a 4N solution of hydrochloric acid.

Les cristaux formés sont récupérés par filtration et séchés. The crystals formed are recovered by filtration and dried.

On obtient, avec un rendement de 75 %, le produit de formule

Figure img00040001
The product of formula is obtained with a yield of 75%
Figure img00040001

Formule brute : C6H6N202
Masse moleculaire : 146,1
Cristaux blancs
Point de fusion : 182"C
Chromatographie sur plaque
- support : gel de silice 60 F 254 Merck
- solvant : chloroforme - méthanol - acide acetique (80/18/2)
- révélation : UV et iode
- Rf : 0,33
III - Preparation du p-chloro phénoxy isobutyrate N-hydroxy
méthyl nicotinamide (Produit dérivé A)
Dans un tricol de 500 ml contenant 38 g (0,25 mole) de Nhydroxymethyl nicotinamide, dans 100 ml de pyridine et 50 ml de
DMF, on ajoute 64,1 g (0,275 mole) de chlorure de p-chlorophénoxy isobutyroyle en solution dans 80 ml de DMF.Gross formula: C6H6N202
Molecular mass: 146.1
White crystals
Melting point: 182 ° C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: chloroform - methanol - acetic acid (80/18/2)
- revelation: UV and iodine
- Rf: 0.33
III - Preparation of N-hydroxy p-chlorophenoxy isobutyrate
methyl nicotinamide (Derived product A)
In a 500 ml three-necked flask containing 38 g (0.25 mol) of N-hydroxymethyl nicotinamide, in 100 ml of pyridine and 50 ml of
DMF, 64.1 g (0.275 mol) of p-chlorophenoxy isobutyroyl chloride dissolved in 80 ml of DMF are added.

On maintient la température à 50C pendant l'addition, puis on laisse deux heures sous forte agitation à température ambiante. Le melange reactionnel est hydrolysé dans deux litres d'eau glacée ; les cristaux obtenus sont repris dans le ch-lorure de méthylène. On décante et on filtre l'insoluble. The temperature is maintained at 50 ° C. during the addition and then left for two hours with vigorous stirring at room temperature. The reaction mixture is hydrolysed in two liters of ice water; the crystals obtained are taken up in methylene chloride. Decant and filter the insoluble.

Le solvant organique est évaporé et le résidu est recristallisé dans un mélange éther isopropylique/acétone. The organic solvent is evaporated and the residue is recrystallized from an isopropyl ether / acetone mixture.

On récupère, avec un rendement de 85 %, le produit de formu

Figure img00050001
85% yield is recovered from the formula product.
Figure img00050001

Formule brute : C17H17ClN204
Masse moléculaire : 348,79
Point de fusion : 110-1110C
Cristaux blancs
Chromatographie sur plaque
- support : gel de silice 60 F 254 Merck
- solvant : methanol - chloroforme 10/90
- révélation :UV et iode
- Rf : 0,48
Spectre IR (KBr) : vNH 3 380 cm , vC=0 ester 1 740 cm
' > C=O amide 1 660 cl~1, vC=C 1 580 cm 1
')C-H deformation/plan substitution para 830cl 1
Spectre RMN (CDCl3/TMS) 6 (ppm) 1,5 (s, 6H,

Figure img00060001

; 5,5 (d, 2H, O-CH2NH) ; 6,8 (quadr., hényle) ; 7,3 (d.d, 1H, pyridine H5)
8,05 (d.d, 1H, pyridine H4) ; 8,2 (t, 1H, NH) ;
8,6 (d.d, 1H, pyridine H6) ; 8,9 (d, 1H, pyridine H2).Gross formula: C17H17ClN204
Molecular weight: 348.79
Melting point: 110-110C
White crystals
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: methanol - chloroform 10/90
- revelation: UV and iodine
- Rf: 0.48
IR spectrum (KBr): vNH 3880 cm, vC = O ester 1740 cm
C = O amide 1660 cl ~ 1, vC = C 1580 cm -1
') CH deformation / substitution plan para 830cl 1
NMR spectrum (CDCl3 / TMS) δ (ppm) 1.5 (s, 6H,
Figure img00060001

; 5.5 (d, 2H, O-CH 2 NH); 6.8 (quadr., Henyl); 7.3 (dd, 1H, pyridine H5)
8.05 (dd, 1H, pyridine H4); 8.2 (t, 1H, NH);
8.6 (dd, 1H, pyridine H6); 8.9 (d, 1H, pyridine H2).

Solubilité : Insoluble dans l'eau ; soluble à 30 % dans le DMSO,
à 15 % dans la méthyl pyrrolidone, à 30 % dans le diméthyl
acétamide et à 5 % dans l'acétate d'éthyle. Solubility: Insoluble in water; 30% soluble in DMSO,
15% in methyl pyrrolidone, 30% in dimethyl
acetamide and 5% in ethyl acetate.

Ce composé chimique a éte soumis à des contrôles de toxicité. This chemical compound has been subjected to toxicity checks.

La DL50 (dose létale) a été étudiée suivant la méthode de Miller et Tainter ; elle est supérieure à 3 000 mg/kg par voie orale.LD50 (lethal dose) was studied according to the method of Miller and Tainter; it is greater than 3000 mg / kg orally.

IV - Préparation du p(chloro-4 benzoyl)-phenoxy isobutyrate
de N-hydroxyméthyl nicotinamide (Produit dérivé B)
En opérant selon le mode opératoire décrit dans l'exemple I, mais en utilisant le chlorure de p(chloro-4 benzoyl) phénoxy isobutyroyle pour traiter le N-hydroxyméthyl nicotinamide, on obtient avec un rendement de 70 à 80 % le produit B, de formule

Figure img00060002
IV - Preparation of p (4-chlorobenzoyl) -phenoxy isobutyrate
of N-hydroxymethyl nicotinamide (Derived product B)
By operating according to the procedure described in Example I, but using p (4-chlorobenzoyl) phenoxy isobutyroyl chloride to treat N-hydroxymethyl nicotinamide, product B is obtained in a yield of 70 to 80%, Formula
Figure img00060002

Formule brute : C24H21ClN205
Masse : 452,9
Chromatographie sur plaque
- support : gel de silice 60 F 254 Merck
- solvant : méthanol - chloroforme 10/90
- révélation : UV et iode
- Rf : 0,4. Gross formula: C24H21ClN205
Mass: 452.9
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: methanol - chloroform 10/90
- revelation: UV and iodine
- Rf: 0.4.

V - Preparation de l' < x((chloro-4 benzoyl aminoéthyl)-4 phe-
noxy3 isobutyrate de N-hydroxyméthyl nicotinamide (Pro
duit C)
En opérant comme précédemment, mais en utilisant le chlorure d'all(chloro-4 benzoylaminoéthyl)-4 phenoxy]isobutyroyle, on recupère, avec un rendement de 75 %, le produit de formule

Figure img00060003
V - Preparation of 4- (4-chloro-benzoyl aminoethyl) -4-phe-
noxy3 isobutyrate N-hydroxymethyl nicotinamide (Pro
duit C)
By operating as above, but using 4- (4-chlorobenzoylaminoethyl) phenoxy] isobutyroyl chloride, the product of formula is recovered with a yield of 75%.
Figure img00060003

Formule brute : C26H26ClN305
Masse moléculaire : 496
Chromatographie sur plaque
- support : gel de silice 60 F 254 Merck
- solvant : méthanol - chloroforme 10/90
- revelation :UV et iode
- Rf : 0,25
VI - Préparation du p-chlorophénoxy isobutyrate de N-hydroxy
nicotinamide (Produit D)
Dans un ballon de 250 ml renfermant une solution de 13,8 g
(0,1 mole) de N-hydroxynicotinamide dans 40 ml de pyridine et 50
ml de DMF, on introduit goutte à goutte 25,6 g (0,11 mole) de
chlorure de p-chlorophénoxy isobutyroyle. La température du
milieu réactionnel est maintenue à 20 C. Gross formula: C26H26ClN305
Molecular weight: 496
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: methanol - chloroform 10/90
- revelation: UV and iodine
- Rf: 0.25
VI - Preparation of N-hydroxy p-chlorophenoxy isobutyrate
Nicotinamide (Product D)
In a 250 ml flask containing a solution of 13.8 g
(0.1 mole) of N-hydroxynicotinamide in 40 ml of pyridine and 50
ml of DMF is added dropwise 25.6 g (0.11 mol) of
p-chlorophenoxy isobutyroyl chloride. The temperature of the
reaction medium is maintained at 20 C.

Après addition, on laisse une nuit à température ambiante,
puis on hydrolyse le mélange réactionnel par 3 litres d'eau gla
cee. Les cristaux formés sont récupérés par filtration et recris
tallises dans l'éther éthylique.After addition, leave overnight at room temperature,
then the reaction mixture is hydrolyzed with 3 liters of water
cee. The crystals formed are recovered by filtration and recreated
tallises in ethyl ether.

On récupère, avec un rendement de 80 %, le produit de formu

Figure img00070001
The product of the formula is recovered with a yield of 80%
Figure img00070001

Formule brute : C16Hl5ClN204
Masse moléculaire : 334,7
Cristaux blancs
Point de fusion : 126"C
Chromatographie sur plaque
- support : gel de silice 60 F 254 Merck
- solvant : méthanol - chloroforme 5/95
- révélation : UV et iode
- Rf : 0,45
Spectre Ir (KBr)

Figure img00070002

1 780 et 1 800 cm-l ;
Figure img00070003

1 690 cm -1
Spectre RMN (DMSO d6 + CDCl3/TMS) 6 (ppm)
1,2 (s, 6H) ; 6,8 à 7,3 (m, 4H) ; 9,1 (d, 1H)
8,7 (m, 1H) ; 8,2 (m, 1H) ; 7,85 (m, 1H) et 11,6 (s, 1H). Gross formula: C16H15ClN204
Molecular weight: 334.7
White crystals
Melting point: 126 ° C
Plate chromatography
- support: silica gel 60 F 254 Merck
- solvent: methanol - chloroform 5/95
- revelation: UV and iodine
- Rf: 0.45
Ir spectrum (KBr)
Figure img00070002

1780 and 1800 cm -1;
Figure img00070003

1,690 cm -1
NMR spectrum (DMSO d6 + CDCl3 / TMS) 6 (ppm)
1.2 (s, 6H); 6.8 to 7.3 (m, 4H); 9.1 (d, 1H)
8.7 (m, 1H); 8.2 (m, 1H); 7.85 (m, 1H) and 11.6 (s, 1H).

Essais pharmacologiques
Les expérimentations pharmacologiques ont permis de mettre en évidence de remarquables propriétés hypolipémiantes et hypocholestérolémiantes. La vérification a été faite sur plusieurs tests prouvant le large spectre d'activité des produits A, B, C, D.Pharmacological tests
Pharmacological experiments have shown remarkable hypolipidemic and hypocholesterolemic properties. The verification was done on several tests proving the broad spectrum of activity of products A, B, C, D.

Ci-après sont rapportés les résultats obtenus avec les produits A, B, C, D, qui ont éte systematiquement comparés aux produits connus de référence : clofibrate, acide nicotinique et Bézafibrate.  The following are the results obtained with the products A, B, C, D, which have been systematically compared to the known reference products: clofibrate, nicotinic acid and bezafibrate.

1. Test portant sur quatre jours de traitement par voie orale
Dans un lot de 30 rats soumis à un régime normal, le 5èe jour sont effectués les prélèvements de sang et les dosages de cholestérol.

Figure img00080001
1. Test for four days of oral treatment
In a batch of 30 rats on a normal diet, the 5th day are made blood samples and cholesterol dosages.
Figure img00080001

<tb><Tb>

Produits <SEP> dosage <SEP> mg/kg <SEP> cholestérol <SEP> % <SEP> variation
<tb> <SEP> par <SEP> rapport <SEP> au <SEP> témoin
<tb> clofibrate <SEP> 200 <SEP> - <SEP> 34
<tb> Ac. <SEP> nicotinique <SEP> 100 <SEP> - <SEP> 22
<tb> Produit <SEP> A <SEP> 100 <SEP> - <SEP> 31
<tb> <SEP> 200 <SEP> - <SEP> 37
<tb> <SEP> 300 <SEP> - <SEP> 50
<tb> Produit <SEP> B <SEP> 100 <SEP> - <SEP> 30
<tb> <SEP> 200 <SEP> - <SEP> 35
<tb> Produit <SEP> C <SEP> 200 <SEP> - <SEP> 28
<tb> Produit <SEP> D <SEP> 100 <SEP> Non <SEP> significatif <SEP> NS
<tb> <SEP> 200 <SEP> - <SEP> 20
<tb> <SEP> 300 <SEP> - <SEP> 35
<tb>
2. Hyperchoîestérolêmie induite par l'administration de
Triton WR 1339
On utilise des lots de rats mâles sur lesquels on prelève un échantillon de sang pour les dosages témoins et sur lesquels on pratique une injection intra-veineuse de Triton, à raison de 200 mg/kg.

Figure img00090001
Products <SEP> Dosage <SEP> mg / kg <SEP> Cholesterol <SEP>% <SEP> variation
<tb><SEP> by <SEP> report <SEP> to <SEP> witness
<tb> clofibrate <SEP> 200 <SEP> - <SEP> 34
<tb> Ac. <SEP> nicotinic <SEP> 100 <SEP> - <SEP> 22
<tb> Product <SEP> A <SEP> 100 <SEP> - <SEP> 31
<tb><SEP> 200 <SEP> - <SEP> 37
<tb><SEP> 300 <SEP> - <SEP> 50
<tb> Product <SEP> B <SEP> 100 <SEP> - <SEP> 30
<tb><SEP> 200 <SEP> - <SEP> 35
<tb> Product <SEP> C <SEP> 200 <SEP> - <SEP> 28
<tb> Product <SEP> D <SEP> 100 <SEP> No <SEP> Significant <SEP> NS
<tb><SEP> 200 <SEP> - <SEP> 20
<tb><SEP> 300 <SEP> - <SEP> 35
<Tb>
2. Hypercholesterolemia induced by the administration of
Triton WR 1339
Batches of male rats on which a blood sample is taken for control dosages and on which an intravenous injection of Triton is administered at 200 mg / kg are used.
Figure img00090001

<tb> Produits <SEP> dosage <SEP> mg/kg <SEP> cholestérol <SEP> g/l
<tb> <SEP> voie <SEP> orale
<tb> témoin <SEP> 2,63 <SEP>
<tb> Bezafibrate <SEP> 100 <SEP> 2,20 <SEP> NS
<tb> Clofibrate <SEP> 200 <SEP> 2,30 <SEP> NS
<tb> <SEP> A <SEP> 50 <SEP> 1,29
<tb> <SEP> 100 <SEP> 1,07
<tb> <SEP> 200 <SEP> 1,19
<tb> <SEP> B <SEP> 200 <SEP> 1,20
<tb> <SEP> C <SEP> 100 <SEP> 1,30
<tb> <SEP> D <SEP> 100 <SEP> 1,90
<tb> <SEP> 200 <SEP> 1,80
<tb> <tb> Products <SEP> assay <SEP> mg / kg <SEP> cholesterol <SEP> g / l
<tb><SEP> way <SEP> oral
<tb> control <SEP> 2.63 <SEP>
<tb> Bezafibrate <SEP> 100 <SEP> 2.20 <SEP> NS
<tb> Clofibrate <SEP> 200 <SEP> 2.30 <SEP> NS
<tb><SEP> A <SEP> 50 <SEP> 1.29
<tb><SEP> 100 <SEP> 1.07
<tb><SEP> 200 <SEP> 1.19
<tb><SEP> B <SEP> 200 <SEP> 1.20
<tb><SEP> C <SEP> 100 <SEP> 1.30
<tb><SEP> D <SEP> 100 <SEP> 1.90
<tb><SEP> 200 <SEP> 1.80
<Tb>

Applications thérapeutiques
Les résultats très probants obtenus en pharmacologie sur le produit A et sa faible toxicité dose létale DL50 > 3 000 mg/kg, ont conduit à mener une étude toxicologique chronique qui devait précéder les essais cliniques.Therapeutic applications
The highly convincing results obtained in pharmacology on product A and its low lethal dose LD50 toxicity> 3000 mg / kg led to a chronic toxicological study that was to precede clinical trials.

Ces essais cliniques ont mis en évidence des proprietés thérapeutiques qui permettent d'utiliser ce produit dans les diffe- rents types d'hyperlipidémies en vue de la prévention et du traitement de l'athérosclérose et de ses conséquences.  These clinical trials have demonstrated therapeutic properties that make it possible to use this product in the various types of hyperlipidemias for the prevention and treatment of atherosclerosis and its consequences.

Claims (13)

REVENDICATIONS 1. A titre de composés chimiques nouveaux, les phénoxy isobutyrates de N-hydroxynicotinamide de formule générale  1. As novel chemical compounds, the N-hydroxynicotinamide phenoxy isobutyrates of the general formula
Figure img00100001
Figure img00100001
 où R = halogène, halogéno benzoyl, where R = halogen, halogeno benzoyl,
Figure img00100002
Figure img00100002
 n = O ou n = 1 et les sels thérapeutiquement acceptables avec des acides minéraux ou organiques ainsi que les N-oxydes correspondants. n = 0 or n = 1 and the therapeutically acceptable salts with inorganic or organic acids and the corresponding N-oxides. 2. p-chlorophénoxy isobutyrate de N-hydroxyméthylnicotinami- de selon la revendication 1. 2. N-hydroxymethylnicotinamide p-chlorophenoxy isobutyrate according to claim 1. 3. p-(chloro-4 benzoyl) phénoxy isobutyrate de N-hydroxyméthylnicotinamide selon la revendication 1. 3. N-Hydroxymethylnicotinamide p- (4-chlorobenzoyl) phenoxy isobutyrate according to claim 1. 4. a Wchloro-4 benzoylaminoethyl)-4 phénoxyisobutyrate d'hydroxymethylnicotinamide selon la revendication 1. 4. 4-chloro-benzoylaminoethyl-4-phenoxyisobutyrate hydroxymethylnicotinamide according to claim 1. 5. p-chlorophenoxy isobutyrate de N-hydroxynicotinamide selon la revendication 1. 5. N-hydroxynicotinamide p-chlorophenoxy isobutyrate according to claim 1. 6. Procédé de préparation du composé chimique selon les revendications 1 et 2, CARACTERISE EN CE QUE l'on traite du N-hy droxyméthylnicotinamide par du chlorure de p-chlorophenoxy isobutyroyle. 6. Process for the preparation of the chemical compound according to claims 1 and 2, CHARACTERIZED IN THAT N-hy droxymethylnicotinamide is treated with p-chlorophenoxy isobutyroyl chloride. 7. Procéde de préparation du composé chimique selon les revendications 1 et 3, CARACTERISE EN CE QUE l'on traite du N-hydroxyméthylnicotinamide par du chlorure de p-(chloro-4 benzoyl) phénoxy isobutyroyle. 7. Process for the preparation of the chemical compound according to claims 1 and 3, CHARACTERIZED IN THAT N-hydroxymethylnicotinamide is treated with p- (4-chlorobenzoyl) phenoxy isobutyroyl chloride. 8. Procéde de préparation du composé chimique selon les revendications 1 et 4, CARACTERISE EN CE QUE l'on traite du N-hy- droxyméthylnicotinamide par du chlorure d'a Echloro-4 benzoyl aminoéthyl )-4 phenoxyisobutyroyle.  8. Process for the preparation of the chemical compound according to claims 1 and 4, CHARACTERIZED IN THAT N-hydroxymethylnicotinamide is treated with 4-chlorobenzoylaminoethyl-4-phenoxyisobutyroyl chloride. 9. Procédé de préparation du composé chimique selon les revendications 1 et 5, CARACTERISE EN CE QUE l'on traite du N-hydroxynicotinamide par du chlorure de p-chlorophénoxy isobutyroyle. 9. Process for the preparation of the chemical compound according to claims 1 and 5, CHARACTERIZED IN THAT the N-hydroxynicotinamide is treated with p-chlorophenoxy isobutyroyl chloride. 10. Applications thérapeutiques des composés chimiques selon l'une quelconque des revendications 1, 2, 3, 4 et 5, notamment pour le traitement des troubles provoqués par l'athérosclérose.  10. Therapeutic applications of the chemical compounds according to any one of claims 1, 2, 3, 4 and 5, especially for the treatment of disorders caused by atherosclerosis. 11. Compositions pharmaceutiques contenant comme principes actifs les composés chimiques selon l'une quelconque des revendications 1,2,3,4 et 5. 11. Pharmaceutical compositions containing as active ingredients the chemical compounds according to any one of claims 1, 2, 3, 4 and 5. 12.Compositions pharmaceutiques selon la revendication 11, 12.Pharmaceutical compositions according to claim 11, CARACTERISEES EN CE QU'elles sont administrées par voie orale.CHARACTERIZED IN THAT they are administered orally. 13. Compositions pharmaceutiques selon les revendications 11 et 12, CARACTERISEES EN CE QU'elles contiennent d'autres principes actifs associés aux composés chimiques des revendications 1,2,3,4 et 5.  13. Pharmaceutical compositions according to claims 11 and 12, CHARACTERIZED IN THAT they contain other active ingredients associated with the chemical compounds of claims 1,2,3,4 and 5.
FR7925279A 1979-10-05 1979-10-05 Hypolipaemic and hypocholesterolaemic ester(s) - of phenoxy-isobutyric acid and N-hydroxy nicotinamide(s) Granted FR2466459A1 (en)

Priority Applications (1)

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FR7925279A FR2466459A1 (en) 1979-10-05 1979-10-05 Hypolipaemic and hypocholesterolaemic ester(s) - of phenoxy-isobutyric acid and N-hydroxy nicotinamide(s)

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FR2466459B1 FR2466459B1 (en) 1982-09-17

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998019555A1 (en) * 1996-11-07 1998-05-14 Milo Olomouc, A.S. Fat with specific antisclerosis effects
WO2008157537A3 (en) * 2007-06-19 2009-04-02 Ironwood Pharmaceuticals Inc Compositions and methods of use for treating or preventing lipid related disorders

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2270878A1 (en) * 1974-05-15 1975-12-12 Fabre Sa Pierre

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2270878A1 (en) * 1974-05-15 1975-12-12 Fabre Sa Pierre

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998019555A1 (en) * 1996-11-07 1998-05-14 Milo Olomouc, A.S. Fat with specific antisclerosis effects
WO2008157537A3 (en) * 2007-06-19 2009-04-02 Ironwood Pharmaceuticals Inc Compositions and methods of use for treating or preventing lipid related disorders

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