CH639072A5 - 2-[ alpha -(p-Chlorophenoxy)isobutyrate] of 2,6-pyridinedimethanol and process for its preparation - Google Patents
2-[ alpha -(p-Chlorophenoxy)isobutyrate] of 2,6-pyridinedimethanol and process for its preparation Download PDFInfo
- Publication number
- CH639072A5 CH639072A5 CH2979A CH2979A CH639072A5 CH 639072 A5 CH639072 A5 CH 639072A5 CH 2979 A CH2979 A CH 2979A CH 2979 A CH2979 A CH 2979A CH 639072 A5 CH639072 A5 CH 639072A5
- Authority
- CH
- Switzerland
- Prior art keywords
- pyridinedimethanol
- acid
- isobutyrate
- chlorophenoxy
- hydrochloride
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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
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Medicinal Preparation (AREA)
Description
is La présente invention concerne le 2-[a-(p-chlorophénoxy)isobutyrate] de 2,6-pyridinediméthanol, de formule développée suivante: The present invention relates to 2- [a- (p-chlorophenoxy) isobutyrate] of 2,6-pyridinedimethanol, of the following structural formula:
CH„ CH „
O-C-COO-CH . 2 O-C-COO-CH. 2
CH- CH-
CH.OH N 2 CH.OH N 2
et ses sels acceptables en pharmacie. Ces sels peuvent être obtenus en particulier à partir d'acides organiques ou inorganiques. On citera notamment le chlorhydrate. and its pharmaceutically acceptable salts. These salts can be obtained in particular from organic or inorganic acids. Mention will in particular be made of the hydrochloride.
L'invention concerne également la préparation de ces composés et des médicaments qui les contiennent. The invention also relates to the preparation of these compounds and medicaments containing them.
Pour obtenir le 2-(p-chlorophénoxy)isobutyrique et du 2,6-pyridinediméthanol, on part de l'acide a-(p-chlorophénoxy)isobu-tyrique et du 2,6-pyridinediméthanol que l'on estérifie en présence d'un catalyseur acide, de préférence un acide sulfonique ou bien l'acide sulfurique. To obtain isobutyric 2- (p-chlorophenoxy) and 2,6-pyridinedimethanol, one starts with a- (p-chlorophenoxy) isobutyric acid and 2,6-pyridinedimethanol which is esterified in the presence of 'An acid catalyst, preferably a sulfonic acid or sulfuric acid.
La réaction est représentée par l'équation suivante: The reaction is represented by the following equation:
H2S04 R-S03H H2S04 R-S03H
n^-ch2°h n ^ -ch2 ° h
<r <r
CH2OH + H20 CH2OH + H20
dans laquelle R représente, bien entendu, le reste de l'acide sulfonique choisi de manière classique, par exemple un reste aliphatique, aromatique, etc. On opère de préférence mole à mole et de préférence dans un milieu non miscible à l'eau, tel que xylène ou toluène. Dans un second stade, on peut former le chlorhydrate ou bien d'autres sels d'acides soit organiques, soit inorganiques, utilisables en thérapeutique. in which R represents, of course, the remainder of the sulfonic acid chosen in a conventional manner, for example an aliphatic, aromatic residue, etc. It is preferably carried out mole to mole and preferably in a medium immiscible with water, such as xylene or toluene. In a second stage, the hydrochloride or other salts of acids, either organic or inorganic, which can be used in therapy, can be formed.
L'exemple suivant illustre l'invention sans toutefois en limiter la portée. The following example illustrates the invention without however limiting its scope.
Exemple I Example I
Préparation du chlorhydrate de 2-[a-(p-chlorophénoxy)isobutyrate] de 2,6-pyridinediméthanol Preparation of 2,6-pyridinedimethanol 2- [a- (p-chlorophenoxy) isobutyrate] hydrochloride
On dissout 128,76 g (0,6 mol) de 2,6-pyridinediméthanol. On chauffe le mélange au reflux à 106-111C dans un ballon tricol muni d'un agitateur, d'un réfrigérant à reflux et d'un séparateur d'eau éliminant celle-ci de la réaction jusqu'à ce qu'il ne se sépare plus d'eau. On verse la solution sur une solution saturée de C03fC2. On lave la phase organique par trois fois 250 ml d'eau, on sèche sur carbonate de potassium anhydre et on élimine le toluène dans un évaporateur rotatif. On dissout le résidu dans l'éthanol absolu en faisant passer su dans la solution alcoolique un courant de chlorure d'hydrogène sec. Le produit précipite par adition d'éther éthylique et on le recristallise dans l'acétate d'éthyle. Rendement 56%. F. 126° C. 128.76 g (0.6 mol) of 2,6-pyridinedimethanol are dissolved. The mixture is heated to reflux at 106-111C in a three-necked flask fitted with a stirrer, a reflux condenser and a water separator eliminating it from the reaction until it does not separates more water. The solution is poured onto a saturated solution of C03fC2. The organic phase is washed with three times 250 ml of water, dried over anhydrous potassium carbonate and the toluene is removed in a rotary evaporator. The residue is dissolved in absolute ethanol by passing a stream of dry hydrogen chloride through the alcoholic solution. The product precipitates by addition of ethyl ether and is recrystallized from ethyl acetate. Yield 56%. Mp 126 ° C.
On obtient des rendements semblables en utilisant comme catalyseur l'acide thymolsulfonique ou d'autres acides sulfoniques. 55 Analyse élémentaire: pour C17Hj8N04C1,HC1 Similar yields are obtained using thymolsulfonic acid or other sulfonic acids as the catalyst. 55 Elementary analysis: for C17Hj8N04C1, HC1
Calculé: C 54,83 H 5,15 N 3,76 Cl 19,06% Calculated: C 54.83 H 5.15 N 3.76 Cl 19.06%
Trouvé: C 54,85 H 5,12 N 3,8 Cl 19,03% Found: C 54.85 H 5.12 N 3.8 Cl 19.03%
Spectre infrarouge: le spectre infrarouge du chlorhydrate est repré-60 sente à la figure unique ci-annexée. Infrared spectrum: the infrared spectrum of the hydrochloride is represented in the single figure attached hereto.
Exemple 2 Example 2
Capsules Quantités par capsule (mg) Capsules Amounts per capsule (mg)
Pirifibrate 375 Pirifibrate 375
w Polyvinylpyrrolidone 20 w Polyvinylpyrrolidone 20
Lactose 21 Lactose 21
Talc 10 Talc 10
Huile de ricin hydrogénée 4 Hydrogenated castor oil 4
3 3
639 072 639,072
Exemple 3 Example 3
Comprimés Quantités par comprimé (mg) Tablets Quantities per tablet (mg)
Pirifibrate 375 Pirifibrate 375
Lactose 500 Lactose 500
Amidon de maïs 100 Corn starch 100
Polyvinylpyrrolidone 20 Polyvinylpyrrolidone 20
Avicel PH-101 65 Avicel PH-101 65
Aerosil 250 15 Aerosil 250 15
Talc 40 Talc 40
CutineHR 10 CutineHR 10
Pharmacologie Pharmacology
On a déterminé la toxicité et l'activité pharmacologique du produit selon l'invention au moyen de divers essais et études phar-macologiques indiqués ci-après. The toxicity and pharmacological activity of the product according to the invention were determined by means of various pharmacological tests and studies indicated below.
Les essais de toxicité aiguë ont montré, pour le produit de l'invention, une toxicité très faible. La DL50 est de 1,25 g/kg par voie orale chez la souris. The acute toxicity tests have shown, for the product of the invention, a very low toxicity. The LD50 is 1.25 g / kg orally in mice.
Les essais de toxicité chronique, à une dose journalière de 200 mg/kg chez des rats Sprague-Dawley pendant 3 mois, par voie orale, n'ont montré aucune différence biologique et histologique significative par rapport à un groupe témoin. Chronic toxicity tests, at a daily dose of 200 mg / kg in Sprague-Dawley rats for 3 months, orally, did not show any significant biological and histological difference compared to a control group.
On a comparé l'évolution de la cholestérolémie et des triglycérides chez le rat tout juste sevré par rapport au Clofibrate et au carba-mate de pyridinol, sur des groupes de huit rats Sprague-Dawley, en condition SPF (environnement général, nourriture, etc., stériles) auxquels on a administré une dose de 400 mg/kg pendant 6 d consécutifs. Les rats utilisés étaient juste sevrés, comme on vient de l'indiquer, et présentaient des valeurs de cholestérolémie naturelle deux à trois fois supérieures à celles obtenues chez les adultes. Les valeurs de cholestérolémie rencontrées sont très inférieures, chez les animaux traités avec le produit selon l'invention, à celles obtenues chez les autres groupes. Les valeurs absolues, exprimées en mg/100 ml, sont les suivantes: We compared the evolution of cholesterolemia and triglycerides in the just weaned rat compared to Clofibrate and carbidate pyridinol, on groups of eight Sprague-Dawley rats, in SPF condition (general environment, food, etc. ., sterile) to which a dose of 400 mg / kg was administered for 6 consecutive d. The rats used were just weaned, as just indicated, and had natural cholesterolemia values two to three times higher than those obtained in adults. The cholesterolemia values encountered are much lower, in animals treated with the product according to the invention, than those obtained in the other groups. The absolute values, expressed in mg / 100 ml, are as follows:
Témoin: 156,25 Witness: 156.25
Carbamate de pyridinol: 123,43 Pyridinol carbamate: 123.43
Clofibrate: 119,44 Clofibrate: 119.44
Produit selon l'invention: 107,81 Product according to the invention: 107.81
On a également effectué une étude comparative de l'action hypo-cholestérolémiante chez le lapin entre le produit selon l'invention, le Clofibrate et le carbamate de pyridinol. Les animaux utilisés sont des lapins New Zealand, pesant 3,5 à 4,0 kg, recevant pendant 8 d, en même temps que le traitement, un régime hypercholestérolémique: on détermine à la fin de l'essai les valeurs de cholestérol total et cholestérol libre, phospholipides, lipides totaux et P-lipoprotéides dans le sérum, selon des techniques spectrophotométriques bien connues, en comparaison avec les valeurs de base et les valeurs obtenues avec les composés témoins. Les doses journalières administrées du produit selon l'invention et des produits comparatifs, Clofibrate et carbamate de pyridinol, sont de 200 mg/kg. Les valeurs obtenues dans ces groupes d'animaux sont comparées entre elles et avec celle d'un groupe témoin hypercholestérolémique sans traitement; on observe des différences notables de diminution des valeurs de cholestérolémie et lipides totaux, principalement dans le groupe d'animaux traités avec le produit selon l'invention. Ces valeurs, exprimées en variation %, sont les suivantes: A comparative study was also carried out of the cholesterol-lowering action in rabbits between the product according to the invention, Clofibrate and pyridinol carbamate. The animals used are New Zealand rabbits, weighing 3.5 to 4.0 kg, receiving for 8 d, at the same time as the treatment, a hypercholesterolemic diet: the total cholesterol values are determined at the end of the test. free cholesterol, phospholipids, total lipids and P-lipoproteides in serum, according to well known spectrophotometric techniques, in comparison with the basic values and the values obtained with the control compounds. The daily doses administered of the product according to the invention and of the comparative products, Clofibrate and pyridinol carbamate, are 200 mg / kg. The values obtained in these groups of animals are compared with each other and with that of a hypercholesterolemic control group without treatment; there are significant differences in the decrease in cholesterolemia and total lipid values, mainly in the group of animals treated with the product according to the invention. These values, expressed as% change, are as follows:
Cholestérol total: Total cholesterol:
Produit selon l'invention = —28,09 Carbamate de pyridinol = +4,3 Clofibrate = —23,68 Product according to the invention = —28.09 Pyridinol carbamate = +4.3 Clofibrate = —23.68
Cholestérol libre: Free cholesterol:
Produit selon l'invention = —13,67 Carbamate de pyridinol = +17,15 Clofibrate = —9,11 Product according to the invention = —13.67 Pyridinol carbamate = +17.15 Clofibrate = —9.11
Lipides totaux: Total fat:
Produit selon l'invention = —19,22 Carbamate de pyridinol = +12,35 Clofibrate = —5,9 Product according to the invention = —19.22 Pyridinol carbamate = +12.35 Clofibrate = —5.9
On a également effectué une étude de la relation dose-effet. Dans ce but, on détermine la cholestérolémie de base chez des groupes de rats Sprague-Dawley auxquels on administre ensuite par voie orale, pendant 4 d consécutifs, des doses journalières du produit selon l'invention et des produits comparatifs, Clofibrate et carbamate de pyridinol, de 100, 200 et 400 mg/kg; on détermine à nouveau la valeur de la cholestérolémie à la fin de cette période de traitement et on exprime les résultats obtenus par une courbe comparative de pourcentage de diminution. Les résultats obtenus montrent des taux de réponse semblables pour le produit selon l'invention et le Clofibrate, supérieurs à celui obtenu pour le carbamate de pyridinol. Les valeurs obtenues sont les suivantes : A dose-response study was also performed. For this purpose, the basic cholesterolemia is determined in groups of Sprague-Dawley rats to which are then administered orally, for 4 consecutive d, daily doses of the product according to the invention and of the comparative products, Clofibrate and pyridinol carbamate. , from 100, 200 and 400 mg / kg; the value of cholesterolemia is again determined at the end of this treatment period and the results obtained are expressed by a comparative curve of percentage decrease. The results obtained show similar response rates for the product according to the invention and Clofibrate, higher than that obtained for pyridinol carbamate. The values obtained are as follows:
Dose journalière (mg/kg) Daily dose (mg / kg)
Produit selon l'invention Product according to the invention
Carbamate de pyridinol Pyridinol carbamate
Clofibrate Clofibrate
100 100
2,60 2.60
1,51 1.51
2,12 2.12
200 200
10,12 10.12
5,60 5.60
9,10 9.10
400 400
23,68 23.68
14,27 14.27
22,06 22.06
De même, on a étudié l'absorption intestinale du produit selon l'invention in situ dans l'intestin de rat. On utilise la technique connue de Doluisio, consistant à mesurer la disparition du médicament administré de l'orifice intestinal, lorsqu'on l'introduit en suspension par perfusion à travers l'intestin isolé in situ du rat. On utilise des rats Sprague-Dawley et on détermine la valeur des échantillons. Ces données permettent de calculer la courbe d'élimination, le temps de séjour moyen (ta Vi = 40 min) et la constante d'absorption (ka = 0,017 min-1)- Ces valeurs d'absorption acceptables coïncident avec leur effet pharmacologique. Likewise, the intestinal absorption of the product according to the invention was studied in situ in the rat intestine. The known Doluisio technique is used, consisting in measuring the disappearance of the drug administered from the intestinal orifice, when it is introduced in suspension by infusion through the intestine isolated in situ from the rat. Sprague-Dawley rats are used and the value of the samples is determined. These data allow the elimination curve, the average residence time (ta Vi = 40 min) and the absorption constant (ka = 0.017 min-1) to be calculated. These acceptable absorption values coincide with their pharmacological effect.
Essais cliniques Clinical tests
La dose journalière du produit selon l'invention chez l'homme est d'environ 1500-3000 mg pour les indications de troubles du métabolisme lipidique, tels que: hyperlipidémie, hypercholestérolémie, hypertriglycéridémie, hyperlipoprotéinémie, Xanthomatose. Traitement prophylactique et étiopathogénique de l'artériosclérose et de ses manifestations cliniques aux niveaux cérébral, coronaire et périphérique. The daily dose of the product according to the invention in humans is approximately 1500-3000 mg for the indications of lipid metabolism disorders, such as: hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipoproteinemia, Xanthomatosis. Prophylactic and etiopathogenic treatment of arteriosclerosis and its clinical manifestations at the cerebral, coronary and peripheral levels.
Les composés selon l'invention peuvent être administrés par voie orale, notamment en comprimés, capsules, etc. Dans l'étude de A. de la Fuente et coll., «Ensayo clinico de un nuevo fàrmaco hipolipe-miante: a-(p-chlorofenoxi)isobutirato de 2-metil-6-(hidroximetil)-piridina», réalisée chez 30 patients qui présentaient des chiffres élevés de lipides totaux, cholestérol et/ou triglycérides, les résultats obtenus montrent une diminution des chiffres de lipides totaux de 14% au terme d'un contrôle de 60 d. Les triglycérides ont diminué de 8,2% chez les patientes et de 19,2% chez les patients. Les pre-ß-lipoprotéines ont diminué de 6,1 % à la fin de ladite période. On n'a pas observé, à la fin du traitement, de différences statistiquement significatives du poids corporel et de la pression artérielle. Les paramètres analytiques biohumoraux examinés ne présentent pas de variation pendant le traitement. La tolérance est qualifiée de bonne; on a observé, dans quatre cas, des troubles gastriques sans influence, pour trois d'entre eux, sur la suite du traitement. The compounds according to the invention can be administered orally, in particular in tablets, capsules, etc. In the study by A. de la Fuente et al., "Ensayo clinico de un nuevo fàrmaco hipolipe-miante: a- (p-chlorofenoxi) isobutirato de 2-metil-6- (hidroximetil) -piridina", carried out in 30 patients who presented high figures of total lipids, cholesterol and / or triglycerides, the results obtained show a reduction of the figures of total lipids of 14% at the end of a control of 60 d. Triglycerides decreased 8.2% in patients and 19.2% in patients. Pre-ß-lipoproteins decreased by 6.1% at the end of said period. There were no statistically significant differences in body weight and blood pressure at the end of treatment. The biohumoral analytical parameters examined show no variation during treatment. Tolerance is described as good; gastric disturbances were observed in four cases, without influence, for three of them, on the continuation of the treatment.
Dans l'étude «Pirifibrate: Nuevo fàrmaco hipolipemiante» de Teigell et coll., on a réalisé une étude double-aveugle randomisée de l'efficacité et de la tolérance du produit selon l'invention en comparaison avec l'alufibrate. Pirifibrate désigne le produit selon l'invention. Les 50 patients prenant part à l'essai présentaient une élévation d'au moins deux des fractions de lipides plasmatiques. In the study “Pirifibrate: Nuevo fàrmaco hipolipemiante” by Teigell et al., A randomized double-blind study of the efficacy and tolerance of the product according to the invention was carried out in comparison with alufibrate. Pirifibrate designates the product according to the invention. All 50 patients in the trial had elevations of at least two of the plasma lipid fractions.
5 5
10 10
15 15
20 20
25 25
30 30
35 35
40 40
45 45
50 50
55 55
60 60
65 65
639 072 639,072
Dans la période de contrôle de 60 d, les variations des chiffres de lipides totaux sont de —10,3% pour les deux médicaments, avec une différence statistiquement significative entre les valeurs initiales et finales des deux groupes, P < 0,005 pour le produit selon l'invention et P < 0,02 pour l'alufibrate. Les triglycérides ont diminué de 8,3% In the 60 d control period, the changes in total lipid counts were -10.3% for the two drugs, with a statistically significant difference between the initial and final values of the two groups, P <0.005 for the product according the invention and P <0.02 for alufibrate. Triglycerides decreased 8.3%
chez les patients traités avec le produit selon l'invention et de 4,6% chez ceux traités à l'alufibrate. Les valeurs de cholestérol ont diminué de 16,5% avec le produit selon l'invention et de 13,2% pour l'alufibrate. On n'a observé aucune altération des paramètres biohu-5 moraux étudiés. in patients treated with the product according to the invention and 4.6% in those treated with alufibrate. The cholesterol values decreased by 16.5% with the product according to the invention and by 13.2% for the alufibrate. No alteration in the biohu-5 moral parameters studied was observed.
R R
1 feuille dessin 1 drawing sheet
Claims (6)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES465758A ES465758A1 (en) | 1978-01-04 | 1978-01-04 | Procedure for obtaining monoester from p-chlorophenoxy-isobutirico acid with 2,6-pyridindimethanol, new pharmacy with hypocolesteramient action. (Machine-translation by Google Translate, not legally binding) |
Publications (1)
Publication Number | Publication Date |
---|---|
CH639072A5 true CH639072A5 (en) | 1983-10-31 |
Family
ID=8475233
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH2979A CH639072A5 (en) | 1978-01-04 | 1979-01-03 | 2-[ alpha -(p-Chlorophenoxy)isobutyrate] of 2,6-pyridinedimethanol and process for its preparation |
Country Status (14)
Country | Link |
---|---|
AT (1) | AT369360B (en) |
BE (1) | BE873280A (en) |
BR (1) | BR7900022A (en) |
CA (1) | CA1114383A (en) |
CH (1) | CH639072A5 (en) |
DE (1) | DE2855811A1 (en) |
ES (1) | ES465758A1 (en) |
FR (1) | FR2414041A1 (en) |
GR (1) | GR69617B (en) |
IT (1) | IT1118259B (en) |
LU (1) | LU80750A1 (en) |
MX (1) | MX5621E (en) |
PH (1) | PH14894A (en) |
PT (1) | PT69024A (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2214511A1 (en) * | 1973-01-19 | 1974-08-19 | Perreau Louis | Suspension of increased storage stability - prepd. by freezing and then thawing of a solid in a liquid |
-
1978
- 1978-01-04 ES ES465758A patent/ES465758A1/en not_active Expired
- 1978-12-18 GR GR57923A patent/GR69617B/el unknown
- 1978-12-18 FR FR7835595A patent/FR2414041A1/en active Granted
- 1978-12-22 DE DE19782855811 patent/DE2855811A1/en not_active Withdrawn
- 1978-12-28 PH PH21998A patent/PH14894A/en unknown
-
1979
- 1979-01-02 LU LU80750A patent/LU80750A1/en unknown
- 1979-01-02 CA CA318,930A patent/CA1114383A/en not_active Expired
- 1979-01-03 BR BR7900022A patent/BR7900022A/en unknown
- 1979-01-03 PT PT69024A patent/PT69024A/en unknown
- 1979-01-03 MX MX797611U patent/MX5621E/en unknown
- 1979-01-03 CH CH2979A patent/CH639072A5/en not_active IP Right Cessation
- 1979-01-03 BE BE2/57529A patent/BE873280A/en not_active IP Right Cessation
- 1979-01-03 IT IT67006/79A patent/IT1118259B/en active
- 1979-01-04 AT AT0006179A patent/AT369360B/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
ES465758A1 (en) | 1978-11-16 |
FR2414041B1 (en) | 1981-07-24 |
ATA6179A (en) | 1982-05-15 |
CA1114383A (en) | 1981-12-15 |
BE873280A (en) | 1979-07-03 |
BR7900022A (en) | 1979-08-07 |
DE2855811A1 (en) | 1979-07-05 |
AT369360B (en) | 1982-12-27 |
FR2414041A1 (en) | 1979-08-03 |
PT69024A (en) | 1979-02-01 |
MX5621E (en) | 1983-11-09 |
PH14894A (en) | 1982-01-08 |
LU80750A1 (en) | 1979-04-13 |
GR69617B (en) | 1982-07-06 |
IT1118259B (en) | 1986-02-24 |
IT7967006A0 (en) | 1979-01-03 |
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