FR2554449A1 - XANTHINE DERIVATIVE - Google Patents
XANTHINE DERIVATIVE Download PDFInfo
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- FR2554449A1 FR2554449A1 FR8410593A FR8410593A FR2554449A1 FR 2554449 A1 FR2554449 A1 FR 2554449A1 FR 8410593 A FR8410593 A FR 8410593A FR 8410593 A FR8410593 A FR 8410593A FR 2554449 A1 FR2554449 A1 FR 2554449A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
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- Veterinary Medicine (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
LE COMPOSE REPONDANT A LA FORMULE(I): (CF DESSIN DANS BOPI) EST UTILE COMME BRONCHO-DILATATEUR ET COMME MUCOLYTIQUE. IL EST PREPARE PAR ESTERIFICATION D'UN DERIVE REACTIF DE L'ACIDE THIOPHENE-2-CARBOXYLIQUE.THE COMPOUND RESPONDING TO FORMULA (I): (CF DRAWING IN BOPI) IS USEFUL AS A BRONCHO-DILATOR AND AS A MUCOLYTIC. IT IS PREPARED BY ESTERIFICATION OF A REACTIVE DERIVATIVE OF THIOPHENE-2-CARBOXYLIC ACID.
Description
ii
DERIVE DE LA XANTHINEXANTHINE DERIVATIVE
La présente invention concerne un nouveau dérivé de la xanthine utile en thérapeutique, un procédé pour sa préparation et des compositions pharmaceutiques le contenant. Le nouveau composé selon la présente invention est la [(thénoyloxy-2)-2-propyl]-7-théophylline répondant à la formule: The present invention relates to a novel xanthine derivative useful in therapy, a process for its preparation and pharmaceutical compositions containing it. The novel compound according to the present invention is [(2-thenoyloxy) -2-propyl] -7-theophylline corresponding to the formula:
": ó, -CHOOC -": ó, -CHOOC -
t'2 y I:you there I:
3 N 33 N 3
N ClH3N ClH3
Contrairement à la théophylline et à d'autres xan- Unlike theophylline and others
thines pour lesquelles l'efficacité thérapeutique est limitée par des effets secondaires, le composé répondant à la formule I possède une activité broncho-dilatatrice et mucolytique utile non associée à des phénomènes tels que la tachycardie et les nausées et vomissements induits thines for which the therapeutic efficacy is limited by side effects, the compound of formula I has useful bronchodilator and mucolytic activity not associated with phenomena such as tachycardia and induced nausea and vomiting
par une irritation gastrique. Il est donc particulière- by gastric irritation. It is therefore particularly
ment utile pour le traitement de maladies respiratoires obstructives telles que la bronchite chronique. Chez l'homme, les doses thérapeutiques utiles du composé sont useful for the treatment of obstructive respiratory diseases such as chronic bronchitis. In humans, the useful therapeutic doses of the compound are
entre 0,2 et 3 g par jour.between 0.2 and 3 g per day.
Selon une caractéristique de la présente invention, la [(thénoyloxy-2)-2propyl]-7-théophylline répondant à la formule I est préparée par un procédé consistant à According to a characteristic of the present invention, [(2-thenoyloxy) -2-propyl] -7-theophylline corresponding to formula I is prepared by a process consisting of
faire réagir la (hydroxy-2-propyl)-7-théophylline répon- react (2-hydroxy-propyl) -7-theophylline with
dant à la formule:to the formula:
O CH2 - CHOHO CH2 - CHOH
2 I2 I
H C < N CH3H C <N CH3
NNOT
CH3 avec un dérivé réactif de l'acide thiophènecarboxylique-2 répondant à la formule: III HOOC Comme dérivé réactif de cet acide carboxylique, on utilise le chlorure, le bromure, un anhydride ou l'imidazolide, qui peuvent être préparés in situ sans isolement ultérieur, ou sont préparés en les isolant CH 3 with a reactive derivative of thiophenecarboxylic acid-2 corresponding to the formula: III HOOC As the reactive derivative of this carboxylic acid, use is made of chloride, bromide, an anhydride or imidazolide, which can be prepared in situ without isolation subsequent, or are prepared by isolating
avant de les faire réagir avec le composé II. before reacting with the compound II.
La réaction est de préférence effectuée à une tempé- The reaction is preferably carried out at a temperature of
rature entre 10 et 90 C dans un solvant organique inerte tel que l'acétone, le dioxane, le chlorure de méthylène, le benzène, le toluène ou la pyridine, et de préférence between 10 and 90 ° C in an inert organic solvent such as acetone, dioxane, methylene chloride, benzene, toluene or pyridine, and preferably
en présence d'une amne tertiaire telle que la triéthylamine. in the presence of a tertiary amine such as triethylamine.
Des compositions pharmaceutiques comprenant comme ingrédient actif la [(thénoyloxy-2)-2-propyl]-7-théophylline Pharmaceutical compositions comprising as active ingredient [(2-thenoyloxy) -2-propyl] -7-theophylline
associée à un excipient ou diluant pharmaceutiquement accep- associated with a pharmaceutically acceptable excipient or diluent
table entrent également dans le cadre de la présente inven- table are also part of the present invention.
tion. Les compositions sont de préférence fabriquées sous une forme convenant pour l'administration orale ou rectale. Les compositions pour l'administration orale peuvent revêtir la forme de comprimés, de capsules, de suspensions ou de poudres et ces préparations peuvent être préparées par des procédés bien connus dans la tion. The compositions are preferably made in a form suitable for oral or rectal administration. The compositions for oral administration may take the form of tablets, capsules, suspensions or powders and these preparations may be prepared by methods well known in the art.
technique et en utilisant des ingrédients usuels. technical and using common ingredients.
Les exemples suivants illustrent la préparation du The following examples illustrate the preparation of the
composé selon la présente invention. compound according to the present invention.
EXEMPLE 1EXAMPLE 1
A une suspension de (hydroxy-2-propyl)-7-théophylline (6,0 g; 0,025 mole) et de triéthylamine (2,5 g; 0,025 To a suspension of (hydroxy-2-propyl) -7-theophylline (6.0 g, 0.025 mole) and triethylamine (2.5 g, 0.025
mole) dans du benzène anhydre (100 ml), on ajoute lente- mole) in anhydrous benzene (100 ml), slowly add
ment une solution de chlorure de thénoyle (3,7 g; 0,025 mole) dans du benzène anhydre (20 ml). On fait bouillir le mélange sous reflux pendant 24 heures, après quoi on élimine le solvant sous vide, on traite le résidu par l'eau et on l'extrait par le chlorure de méthylène. On lave la solution organique avec une solution aqueuse de bicarbonate de sodium, on la sèche, on la décolore et on élimine le solvant sous vide, ce qui fournit un résidu cireux qui se solidifie par traitement avec de l'éther a solution of thenoyl chloride (3.7 g, 0.025 mol) in anhydrous benzene (20 ml). The mixture was boiled under reflux for 24 hours, after which the solvent was removed in vacuo, the residue was treated with water and extracted with methylene chloride. The organic solution is washed with aqueous sodium bicarbonate solution, dried, decolorized and the solvent removed in vacuo to provide a waxy residue which solidifies by treatment with ether.
diéthylique. On obtient la [(thénoyloxy-2)-2-propyl]-7- diethyl. We obtain [(2-thenoyloxy) -2-propyl] -7-
théophylline (5,5 g) qui fond à 142-144 C apres recris- theophylline (5.5 g) melting at 142-144 ° C after recreating
tallisation dans de l'éthanol.in ethanol.
EXEMPLE 2EXAMPLE 2
On agite un mélange de benzène (20 ml) de N,N- A mixture of benzene (20 ml) of N, N-
diméthyl-formamide (3,6 ml) et de chlorure de thionyle (3 ml) à la température ambiante pendant dix minutes (il se forme deux couches) et on ajoute lentement le dimethylformamide (3.6 ml) and thionyl chloride (3 ml) at room temperature for ten minutes (two layers are formed) and slowly added
mélange obtenu à une solution d'acide thiophènecarboxy- mixture obtained with a solution of thiophenecarboxylic acid
lique-2 (5,12 g; 0,04 mole) dans du benzène (25 ml). lique-2 (5.12 g, 0.04 mol) in benzene (25 ml).
Après avoir agité à la température ambiante pendant After stirring at room temperature for
minutes, on ajoute lentement la solution à une sus- minutes, the solution is slowly added to a
pension de (hydroxy-2-propyl)-7-théophylline (9,5 g; 0,04 mole) et de triéthylamine (4,04 g; 0,04 mole) dans du benzène (125 ml). On fait bouillir le mélange sous reflux pendant 24 heures, après quoi on isole le composé (2-Hydroxypropyl) -7-theophylline (9.5 g, 0.04 mol) and triethylamine (4.04 g, 0.04 mol) in benzene (125 ml). The mixture is boiled under reflux for 24 hours, after which the compound is isolated
comme il est décrit dans l'exemple 1. as described in Example 1.
EXEMPLE 3EXAMPLE 3
A une suspension de (hydroxy-2-propyl)-7-théophylline (11,9 g; 0,05 mole) dans du dioxane (100 ml), on ajoute une solution d'anhydride thiophènecarboxylique-2 (13,1 g; 0,055 mole) dans du dioxane (20 ml). On agite le mélange To a suspension of (hydroxy-2-propyl) -7-theophylline (11.9 g, 0.05 mol) in dioxane (100 ml) is added a solution of thiophenecarboxylic anhydride-2 (13.1 g; 0.055 moles) in dioxane (20 ml). Stir the mixture
obtenu à 80 C pendant 6 heures, après quoi on le refroi- obtained at 80 C for 6 hours, after which it is cooled
dit et on le verse dans de l'eau froide. Tout en agitant, on ajoute une solution aqueuse saturée de bicarbonate de said and poured in cold water. While stirring, a saturated aqueous solution of sodium bicarbonate
sodium jusqu'à un pH alcalin, on filtre le solide insolu- sodium to an alkaline pH, the solid
ble et on le lave à l'eau. On obtient la [(thénoyloxy-2)- ble and washed with water. We obtain [(2-thenoyloxy) -
2-propyl]-7-théophylline (13,4 g) qui fond à 143-144 C. 2-propyl] -7-theophylline (13.4 g) melting at 143-144 ° C.
EXEMPLE 4EXAMPLE 4
A une solution d'imidazole (7,7 g; 0,113 mole) dans du chlorure de méthylène (80 ml) on ajoute de l'acide thiophènecarboxylique-2 (3,84 g; 0, 03 mole). On ajoute du chlorure de thionyle (3,33 g; 0,028 mole) à une tem- pérature inférieure à 10 C, puis on fait bouillir le To a solution of imidazole (7.7 g, 0.113 mol) in methylene chloride (80 ml) was added thiophenecarboxylic acid-2 (3.84 g, 0.03 mol). Thionyl chloride (3.33 g, 0.028 mol) is added at a temperature below 10 ° C, and then the mixture is boiled.
mélange obtenu sous reflux pendant 2,5 heures. Apres re- mixture obtained under reflux for 2.5 hours. After
froidissement à 15 C, on ajoute de la (hydroxy-2-propyl)- cooled to 15 C, added (2-hydroxypropyl) -
7-théophylline (5,48 g; 0,023 mole) et on fait bouillir le mélange sous reflux pendant trois heures, on le verse sur une solution aqueuse de bicarbonate de sodium et on le décante. On lave la solution organique avec de l'eau et on élimine le solvant sous vide, ce qui donne un résidu que l'on traite par l'éther diéthylique. On obtient la [(thénoyloxy-2)-2propyl]-7-théophylline (6,9 g), 7-theophylline (5.48 g, 0.023 mol) and the mixture was boiled under reflux for three hours, poured onto aqueous sodium bicarbonate solution and decanted. The organic solution is washed with water and the solvent removed in vacuo to give a residue which is treated with diethyl ether. [(2-Thenoyloxy) -2-propyl] -7-theophylline (6.9 g) is obtained,
point de fusion 143-144 C.melting point 143-144C.
EXEMPLE 5EXAMPLE 5
A une solution froide de (hydroxy-2-propyl)-7- To a cold solution of (hydroxy-2-propyl) -7-
théophylline (4980 g; 20,9 moles) dans de la pyridine (10,5 litres) on ajoute lentement du chlorure de thénoyle (3063 g; 20,9 moles). Apres avoir agité pendant 15 heures à la température ambiante, on verse le mélange dans de l'eau (100 litres) et on filtre le solide qui précipite, on le lave soigneusement à l'eau et on le sèche. On obtient la [(thénoyloxy-2)-2-propyl]-7-théophylline (7684 g) qui fond à 143-144 C après recristallisation theophylline (4980 g, 20.9 mol) in pyridine (10.5 liters) thenoyl chloride (3063 g, 20.9 mol) was slowly added. After stirring for 15 hours at room temperature, the mixture is poured into water (100 liters) and the solid which precipitates is filtered off, washed well with water and dried. [(Thenoyloxy-2) -2-propyl] -7-theophylline (7684 g) is obtained which melts at 143-144 ° C. after recrystallization.
dans l'isopropanol.in isopropanol.
Les exemples suivants illustrent des compositions The following examples illustrate compositions
pharmaceutiques conformes à l'invention. pharmaceutical compositions according to the invention.
EXEMPLE 6EXAMPLE 6
On prépare 1000 litres d'une suspension contenant 450 mg de [(thénoyloxy2)-2-propyl]-7-théophylline pour ml à partir de la formule suivante: [(thénoyloxy-2)-2-propyl]-7-théophylline (sous forme de granulés enrobés) 90 kg cellulose microcristalline 10 kg méthylcellulose 4 kg Solution de sorbitol (70 %) 300 kg saccharine sadique 1 kg parfum 2kg eau purifiée, q. s. pour donner 1000 1 On disperse la cellulose microcristalline et la méthylcellulose dans 150 litres d'eau, on fait passer la suspension dans un broyeur colloïdal et on ajoute une solution aqueuse de saccharine sodique, de parfum et de sorbitol. Puis on ajoute les granulés enrobés de [(thénoyloxy-2)-2-propyl]-7-théophylline et on complète 1000 liters of a suspension containing 450 mg of [(thenoyloxy) -2-propyl] -7-theophylline per ml are prepared from the following formula: [(2-thenoyloxy) -2-propyl] -7-theophylline ( in the form of coated granules) 90 kg microcrystalline cellulose 10 kg methylcellulose 4 kg Sorbitol solution (70%) 300 kg sadistic saccharin 1 kg perfume 2kg purified water, q. s. to give 1000 microcrystalline cellulose and methylcellulose are dispersed in 150 liters of water, the suspension is passed through a colloid mill and an aqueous solution of sodium saccharin, perfume and sorbitol is added. Then the granules coated with [(2-thenoyloxy) -2-propyl] -7-theophylline are added and
le mélange à 1000 litres avec de l'eau désionisée. the mixture at 1000 liters with deionized water.
EXEMPLE 7EXAMPLE 7
On prépare des granulés enrobés de [(thénoyloxy-2)- Granules coated with [(2-thenoyloxy) -
2-propyl]-7-théophylline de la manière suivante: 2-propyl] -7-theophylline as follows:
On granule une partie de [(thénoyloxy-2)-2-propyl]- Part of [(2-thenoyloxy) -2-propyl] is granulated
7-théophylline et quatre parties de lactose dans un 7-theophylline and four parts of lactose in one
mélangeur ultrarapide en utilisant de la polyvinylpyrro- ultrafast mixer using polyvinylpyrrolidine
lidone comme agglutinant et de l'eau comme agent de mélange. On fait passer les granules séchés à travers un tamis ayant une ouverture de maille de 0,42 mm et on les lidone as a clumping agent and water as a blending agent. The dried granules are passed through a sieve having a mesh size of 0.42 mm and
micro-enrobe par séchage par pulvérisation à une tempé- micro-coating by spray drying at a temperature of
rature de 85 C et sous une pression de 5884 kpa. Enfin, on sèche les granulés obtenus à 50 C et on les tamise at 85 C and under a pressure of 5884 kpa. Finally, the granules obtained are dried at 50 ° C. and sieved.
à travers un tamis de 0,25 mm d'ouverture de maille. through a sieve of 0.25 mm mesh opening.
Comme agent d'enrobage, on utilise la suspension suivante: phtalate d'hydroxypropylcellulose 60 g triacétine 10 g polysorbate 80 4g talc 20 g isopropanol 700 ml eau désionisée, q.s. pour 1000 ml As coating agent, the following suspension is used: hydroxypropylcellulose phthalate 60 g triacetin 10 g polysorbate 80 4g talc 20 g isopropanol 700 ml deionized water, q.s. for 1000 ml
EXEMPLE 8EXAMPLE 8
On prépare 1000 comprimés contenant chacun 450 mg de [(thénoyl-2)-2propyl]-7)théophylline à partir de la formule suivante: [(thénoyloxy-2)-2propyl] -7-théophylline 450 g amidon de.mals 200 g lactose monohydrate 100 g 1000 tablets each containing 450 mg of [(2-thénoyl) -2-propyl] -7-theophylline are prepared from the following formula: [(2-thenoyloxy) -2-propyl] -7-theophylline 450 g 200 g starch lactose monohydrate 100 g
solution aqueuse à 5 % de polyvinyl- 5% aqueous solution of polyvinyl
pyrrolidone 45 g carboxyméthyl amidon 40 g stéaryl fumarate de sodium 8 g pyrrolidone 45 g carboxymethyl starch 40 g sodium stearyl fumarate 8 g
On mélange à la [ (thénoyloxy-2)-2-propyl]-7- Mixed with [(2-thenoyloxy) -2-propyl] -7-
théophylline, l'amidon de mais, le lactose monohydrate et la polyvinylpyrrolidone et on fait passer le granulé obtenu à travers un tamis ayant une ouverture de maille de 2 mm et on le sèche à 60 C. Puis on le fait passer à nouveau à travers un tamis ayant une ouverture de maille de 0,84 mm et on ajoute le carboxyméthyl amidon et le stéaryl fumarate de sodium. On comprime le mélange obtenu theophylline, corn starch, lactose monohydrate and polyvinylpyrrolidone and the resulting granulate is passed through a sieve having a mesh size of 2 mm and dried at 60 C. Then it is passed again through a sieve having a mesh size of 0.84 mm and carboxymethyl starch and sodium stearyl fumarate are added. The resulting mixture is compressed
en comprimés de 810 mg.in tablets of 810 mg.
EXEMPLE 9EXAMPLE 9
On prépare 10.000 suppositoires contenant chacun 650 mg de [(thénoyloxy-2) -2-propyl]-7-théophylline de la manière suivante: [(thénoyloxy-2)-2propyl]-7-théophylline 6.500 g huile de théobroma 13.500 g On fond l'huile de théobroma et le composé actif qui s'y trouve en suspension. On verse ensuite le mélange dans un moule à suppositoire approprié pour faire des 10,000 suppositories each containing 650 mg of [(2-thenoyloxy) -2-propyl] -7-theophylline were prepared as follows: [(2-thenoyloxy) -2-propyl] -7-theophylline 6,500 g theobroma oil 13,500 g theobroma oil and the active compound suspended therein. The mixture is then poured into a suitable suppository mold to make
suppositoires de 2,0 g.suppositories of 2.0 g.
Claims (14)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES523854A ES8502113A1 (en) | 1983-07-05 | 1983-07-05 | Xanthine derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
FR2554449A1 true FR2554449A1 (en) | 1985-05-10 |
Family
ID=8485967
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
FR8410593A Withdrawn FR2554449A1 (en) | 1983-07-05 | 1984-07-04 | XANTHINE DERIVATIVE |
Country Status (7)
Country | Link |
---|---|
JP (1) | JPS6084290A (en) |
KR (1) | KR850001197A (en) |
DE (1) | DE3424620A1 (en) |
ES (1) | ES8502113A1 (en) |
FR (1) | FR2554449A1 (en) |
GB (1) | GB2143233A (en) |
IT (1) | IT1180197B (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2097015A1 (en) * | 1970-07-27 | 1972-03-03 | Investigations Sci Pharm | Esters of 7-(2,3-dihydroxypropyl)theophylline - cardiovascular and respiratory system active |
EP0049494A1 (en) * | 1980-10-03 | 1982-04-14 | King Consult GmbH | Esters of 7-hydroxyalkyl-1,3-dimethyl xanthines, process for their preparation and their application as lipid diminishers |
-
1983
- 1983-07-05 ES ES523854A patent/ES8502113A1/en not_active Expired
-
1984
- 1984-07-04 FR FR8410593A patent/FR2554449A1/en not_active Withdrawn
- 1984-07-04 KR KR1019840003861A patent/KR850001197A/en not_active Application Discontinuation
- 1984-07-04 DE DE19843424620 patent/DE3424620A1/en not_active Withdrawn
- 1984-07-04 GB GB08417008A patent/GB2143233A/en not_active Withdrawn
- 1984-07-04 JP JP59137377A patent/JPS6084290A/en active Pending
- 1984-07-04 IT IT21743/84A patent/IT1180197B/en active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2097015A1 (en) * | 1970-07-27 | 1972-03-03 | Investigations Sci Pharm | Esters of 7-(2,3-dihydroxypropyl)theophylline - cardiovascular and respiratory system active |
EP0049494A1 (en) * | 1980-10-03 | 1982-04-14 | King Consult GmbH | Esters of 7-hydroxyalkyl-1,3-dimethyl xanthines, process for their preparation and their application as lipid diminishers |
Also Published As
Publication number | Publication date |
---|---|
KR850001197A (en) | 1985-03-16 |
GB8417008D0 (en) | 1984-08-08 |
IT8421743A0 (en) | 1984-07-04 |
GB2143233A (en) | 1985-02-06 |
ES523854A0 (en) | 1984-12-16 |
IT8421743A1 (en) | 1986-01-04 |
IT1180197B (en) | 1987-09-23 |
DE3424620A1 (en) | 1985-01-17 |
ES8502113A1 (en) | 1984-12-16 |
JPS6084290A (en) | 1985-05-13 |
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