FR2491926A1 - Raubasine (ajmalicine or delta-yohimbine) anti-anoxic derivs. - used for treat cerebral vascular damage, cerebral sclerosis, cranial trauma disorders and depressive states - Google Patents
Raubasine (ajmalicine or delta-yohimbine) anti-anoxic derivs. - used for treat cerebral vascular damage, cerebral sclerosis, cranial trauma disorders and depressive states Download PDFInfo
- Publication number
- FR2491926A1 FR2491926A1 FR8021643A FR8021643A FR2491926A1 FR 2491926 A1 FR2491926 A1 FR 2491926A1 FR 8021643 A FR8021643 A FR 8021643A FR 8021643 A FR8021643 A FR 8021643A FR 2491926 A1 FR2491926 A1 FR 2491926A1
- Authority
- FR
- France
- Prior art keywords
- radical
- sep
- alkoxycarbonyl
- acid
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
La présente invention a pour objet des dérivés de raubasine, leur préparation et leur application en thérapeutique.The present invention relates to raubasin derivatives, their preparation and their therapeutic application.
Dans le brevet n 79 25353 ont été décrits des dérivés de l'acide oxayohimbane-carboxylique portant un groupe R sur l'azote du noyau indolique. i
La Demanderesse a poursuivi ses recherches dans ce domaine et préparé plusieurs nouveaux dérivés de la raubasine.In Patent No. 79 25353 there have been described derivatives of oxayohimbanecarboxylic acid carrying a group R on the nitrogen of the indole nucleus. i
The Applicant has continued his research in this area and prepared several new derivatives of raubasine.
Les composés répondent à la formule (I)
dans laquelle
R1 est un atome d'hydrogène,
un radical (C1-4)-alcoxycarbonyle,
un radical phénoxycarbonyle dont le phényle peut porter
un atome d'halogène ou un groupe nitro,
un radical (C1-4)-acyle,
un radical (C1-4)-alcoxycarbonyle-(C1-4)-alkyle,
R2 est un radical OMe (Me = métal alcalin ou alcalinoterreux),
un radical (C2 4)-alcoxy droit ou ramifié,
un radical (C3-6) -cycloalkyl- (C14) -alcoxy,
un radical (C3-6)-cycloalcoxy,
le radical amino,
un radical (C1-4)-alkylamino,
un radical di (Cl 4)-alkyl-amino,
un radical (C3-6)-cycloalkyl-amino,
Les sels d'addition des composés (I) aux acides pharmaceutiquement acceptables font partie de l'invention.The compounds correspond to formula (I)
in which
R1 is a hydrogen atom,
a (C1-4) -alkoxycarbonyl radical,
a phenoxycarbonyl radical whose phenyl may carry
a halogen atom or a nitro group,
a (C1-4) -acyl radical,
a (C1-4) -alkoxycarbonyl- (C1-4) -alkyl radical,
R2 is an OMe radical (Me = alkali metal or alkaline earth metal),
a radical (C2 4) -alkoxy straight or branched,
a (C 3-6) -cycloalkyl- (C 14) -alkoxy radical,
a (C 3-6) -cycloalkoxy radical,
the amino radical,
a (C1-4) -alkylamino radical,
a di (Cl 4) -alkyl-amino radical,
a (C3-6) -cycloalkyl-amino radical,
The addition salts of compounds (I) with pharmaceutically acceptable acids form part of the invention.
Les composés préférés de l'invention sont ceux dans lesquels
R1 est un radical alcoxycarbonyle ou un radical alcoxycarbonylalkyle.The preferred compounds of the invention are those in which
R 1 is an alkoxycarbonyl radical or an alkoxycarbonylalkyl radical.
La matière de départ est la raubasine (ou ajmalicine) (R1=H,
R2=OCHE).The starting material is raubasin (or ajmalicin) (R1 = H,
R2 = OCHE).
On peut également utiliser comme matière de départ une base quaternaire pseudo-aromatique,la serpentine et réduire cette dernière par hydrogénationcatalytique ou par un borohydrure de métal alcalin en un composé tétrahydrogéné.A pseudoaromatic quaternary base, serpentine, can also be used as starting material and the latter can be reduced by catalytic hydrogenation or by an alkali metal borohydride to a tetrahydrogenated compound.
Selon l'invention on peut preparer les composés de la manière suivante
On prépare l'acide I (R1=H, R2=OH) à partir de la raubasine (R1=H, R2=CH3O) par saponification. On peut obtenir les esters (I) selon des méthodes classiques, notamment soit par estéri fiction directe de l'acide, (par reaction entre le chlorure d'acide et l'alcool R2H ou un de ses sels alcalins) soit par transestérification de la raubasine.According to the invention, the compounds can be prepared in the following manner
Acid I (R1 = H, R2 = OH) is prepared from raubasin (R1 = H, R2 = CH3O) by saponification. The esters (I) can be obtained by conventional methods, in particular either by direct esterification of the acid, (by reaction between the acid chloride and the R2H alcohol or an alkaline salt thereof) or by transesterification of the raubasine.
On obtient les amides (I) à partir de l'acide (I) R1=H, R2=OH) ou de l'un de ses dérivés fonctionnels par amidification classique.The amides (I) are obtained from the acid (I) R1 = H, R2 = OH) or from one of its functional derivatives by conventional amidification.
Les composés (I) portant un radical Rlf H sont obtenus à partir des composés (I) dans lesquels R1 est H par reaction du composé avec un halogénure d'alcoxycarbonyle ou d'alcoxycarbonylalkyle, c'est à dire que l'on forme l'anion de la raubasine, par exemple par solubilisation de la base dans du diméthylformamide et action de l'hydrure de sodium, puis on ajoute alors le composé
R1X (X= Cl ou Br). Compounds (I) carrying a radical Rlf H are obtained from compounds (I) in which R1 is H by reacting the compound with an alkoxycarbonyl or alkoxycarbonylalkyl halide, ie forming the anion of raubasin, for example by solubilization of the base in dimethylformamide and action of sodium hydride, and then the compound is added
R1X (X = Cl or Br).
La réaction est effectuée à une température de O à 200C. The reaction is carried out at a temperature of 0 to 200C.
Les exemples suivants. illustrent l'invention.The following examples. illustrate the invention.
Les analyses et les spectres IR et RMN confirment la structure des composés.Analyzes and IR and NMR spectra confirm the structure of the compounds.
EXEMPLE 1 Ethylamide de l'acide méthoxycarbonyl-l didéhydro
16,17 méthyl-l9 α oxayohimbane-carboxylique.
EXAMPLE 1 Ethylamide of methoxycarbonyl-1 didehydro acid
16.17 methyl-19 α oxayohimbane-carboxylic acid.
<tb><Tb>
[R1 <SEP> - <SEP> COOCH3, <SEP> R2 <SEP> - <SEP> @@C2H5]
<tb> 1. Acide oxayohimbane carboxylique didéhydro-16,17 méthyl-19 α. [R1 <SEP> - <SEP> COOCH3, <SEP> R2 <SEP> - <SEP> @@ C2H5]
<tb> 1. Oxayohimbane carboxylic acid didehydro-16,17 methyl-19 α
On fait réagir 60 g (0,170 mole) de raubasine, en solution dans 2 1 de méthanol et 1 1 d'eau, avec 31. g de soude (0,785 mole).60 g (0.170 mol) of raubasin, dissolved in 2 l of methanol and 1 l of water, are reacted with 31 g of sodium hydroxide (0.785 mol).
On porte le mélange réactionnel pendant 19 heures à la température du reflux.The reaction mixture is heated at reflux temperature for 19 hours.
Après évaporation du méthanol, on acidifie le mélange avec de l'acide chlorhydrique. On filtre le produit précipité et on le lave à l'eau. Après chromatographie sur gel de silice on obtient l'acide que l'on fait recristalliser dans un mélange
CH2Cl2/CH3OH (1/1).
After evaporation of the methanol, the mixture is acidified with hydrochloric acid. The precipitated product is filtered and washed with water. After chromatography on silica gel, the acid is obtained which is recrystallized from a mixture
CH2Cl2 / CH3OH (1/1).
<tb><Tb>
F <SEP> = <SEP> 205 C <SEP> [α]# <SEP> <SEP> = <SEP> -41,5 <SEP> (c=0,6
<tb> pyridine 2. Ethylamide de l'acide didéhydro-16,11 méthyl-19 α α oxayohim-
bane carboxylique.F <SEP> = <SEP> 205 C <SEP>[α]#<SEP><SEP> = <SEP> -41.5 <SEP> (c = 0.6
<tb> pyridine 2. Ethylamide of 16,11-didehydro-16-methyl-α-acid; α oxayohim-
carboxylic acid.
On prépare d'abord le chlorure de l'acide par réaction de ce dernier (25 g) en solution dans du chloroforme (1 1) en présenc de pyridine (9 cm ) avec du chlorure d'oxalye (23 cm ) en solution dans du chloroforme sec (25 cm ). Le réaction est effectuée à froid. On porte le mélange réactionnel pendant 2 heures à la température du reflux.The acid chloride is first prepared by reaction of the latter (25 g) in solution in chloroform (1 1) in the presence of pyridine (9 cm) with oxaloyl chloride (23 cm) in solution in dry chloroform (25 cm). The reaction is carried out cold. The reaction mixture is heated for 2 hours at reflux temperature.
On ajoute 7 g d'êthylamine. 7 g of ethylamine are added.
On laisse revenir le mélange réactionnel à la température ambiante et on l'agite pendant 1 heure.The reaction mixture was allowed to warm to room temperature and stirred for 1 hour.
On ajoute alors de l'eau, décante et extrait au chloroforme. Water is then added, decanted and extracted with chloroform.
On lave la phase organique avec de l'eau puis la sèche sur
MgSO4. On évapore à siccité et obtient un solide que l'on fait recristalliser dans un mélange CH3OH/CH3Cl2.
The organic phase is washed with water and then dried over
MgSO4. It is evaporated to dryness and a solid is obtained which is recrystallized from a CH3OH / CH3Cl2 mixture.
<tb><Tb>
F <SEP> = <SEP> 267-8 C <SEP> (dec) <SEP> [α]# <SEP> = <SEP> -28,7 <SEP> <SEP> (C=1,65 <SEP> CH3OH)
<tb> 3. Ethylamide de l'acide méthoxycarbonyl-l didéhydro-16,17
méthyl-19α oxayohimbane-carboxylique.F <SEP> = <SEP> 267-8 C <SEP> (dec) <SEP>[α]#<SEP> = <SEP> -28.7 <SEP><SEP> (C = 1.65 <SEP> CH3OH)
<tb> 3. Ethylamide of methoxycarbonyl-1-didehydro-16,17
methyl-19 α oxayohimbane-carboxylic acid.
On fait réagir 2 g du produit obtenu orécédemment sous 2, sous forme de chlorhydrate, en solution dans 40 cm3 de diméthylformamide, en présence de 1 g (0,019 mole) d'hydrure de sodium à 50% avec 1,5 cm3 (0,019 mole) de chloroformiate de méthyle sous argon.2 g of the product obtained previously under 2, in hydrochloride form, are dissolved in 40 cm 3 of dimethylformamide in the presence of 1 g (0.019 mol) of 50% sodium hydride with 1.5 cm 3 (0.019 mol). ) of methyl chloroformate under argon.
Après avoir agité, on ajoute de l'eau, extrait avec de l'oxyde de diethyle, lave à l'eau glacée plusieurs fois et sèche sur
MgSO4. Après évaporation à sec, le produit cristallise. Après recristallisation dans un mélange CH2Cl2/(C2H5)2O, il fond à 168-90C.
After stirring, add water, extract with diethyl ether, wash with ice water several times and dry on
MgSO4. After evaporation to dryness, the product crystallizes. After recrystallization from CH2Cl2 / (C2H5) 2O, it melts at 168-90C.
<tb><Tb>
[α]# <SEP> <SEP> = <SEP> - <SEP> 192,7 <SEP> (c=0,7, <SEP> CH3OH)
<tb>
TABLEAU
[α]#<SEP><SEP> = <SEP> - <SEP> 192.7 <SEP> (c = 0.7, <SEP> CH3OH)
<Tb>
BOARD
<tb> Composé <SEP> R1 <SEP> R2 <SEP> F <SEP> ( C) <SEP> [α]#
<tb> <SEP> 1 <SEP> H <SEP> OC4H9 <SEP> HCl-300 <SEP> -9,5 <SEP> (c=0,8
<tb> <SEP> CH3OH)
<tb> <SEP> 2 <SEP> H <SEP> NHC2H5 <SEP> HCl-267-8 <SEP> -28,7 <SEP> (c=1,7
<tb> <SEP> CH3OH)
<tb> <SEP> 3 <SEP> COOCH3 <SEP> NHC2H5 <SEP> Base-168-9 <SEP> -192,7 <SEP> (c=0,7
<tb> <SEP> CH3OH). <SEP>
<tb> <tb> Compound <SEP> R1 <SEP> R2 <SEP> F <SEP> (C) <SEP>[α]#
<tb><SEP> 1 <SEP> H <SEP> OC4H9 <SEP> HCl-300 <SEP> -9.5 <SEP> (c = 0.8
<tb><SEP> CH3OH)
<tb><SEP> 2 <SEP> H <SEP> NHC2H5 <SEP> HCl-267-8 <SEP> -28.7 <SEP> (c = 1.7
<tb><SEP> CH3OH)
<tb><SEP> 3 <SEP> COOCH3 <SEP> NHC2H5 <SEP> Base-168-9 <SEP> -192.7 <SEP> (c = 0.7
<tb><SEP> CH3OH). <September>
<Tb>
Les composés de l'invention ont été soumis à des essais pharmacologiques.The compounds of the invention have been subjected to pharmacological tests.
La toxicité des composés a été déterminée par voie intrapéritonéale sur des souris.The toxicity of the compounds was determined intraperitoneally in mice.
La DL 50 varie de 300 à 1000 mg/kg. The LD 50 varies from 300 to 1000 mg / kg.
Les composés ont été soumis au test de l'anoxie hypobare.The compounds were subjected to the hypobaric anoxia test.
Des souris de souche CDî sont maintenues dans une atmosphère appauvrie en oxygène, par réalisation d'un vide partiel (190 mm de mercure correspondant à 5,25% d'oxygène). CD1 strain mice are maintained in an oxygen-depleted atmosphere by performing a partial vacuum (190 mm Hg corresponding to 5.25% oxygen).
Le temps de survie des animaux est noté. Ce temps est augmenté par les agents capables de favoriser l'oxygénation tissulaire et en particulier cérébrale. Les composés étudiés sont administrés, à plusieurs doses, par voie intrapéritonéale, 10 minutes avant l'essai. Les pourcentages d'augmentation du temps de survie par rapport aux valeurs obtenues chez les animaux témoins sont calculés. La dose active moyenne (DAM), dose qui augmente le temps de survie de 100% est déterminée graphiquement.The survival time of the animals is noted. This time is increased by the agents capable of promoting tissue oxygenation and in particular cerebral oxygenation. The compounds studied are administered, in several doses, intraperitoneally, 10 minutes before the test. The percentages of increase of the survival time compared to the values obtained in the control animals are calculated. The mean active dose (AMD), which increases the survival time by 100%, is determined graphically.
La DAM des composés de l'invention varie de 10 à 60 mg/kg par voie i.p.The DAM of the compounds of the invention ranges from 10 to 60 mg / kg i.p.
L'étude pharmacologique des composés de l'invention montre qu'ils sont actifs dans l'épreuve d'anoxie hypobare chez la souris tout en n'étant que peu toxiques.The pharmacological study of the compounds of the invention shows that they are active in the test of hypobaric anoxia in mice while being only slightly toxic.
Les composés de l'invention, possédant une activité antiano xique, peuvent être utilisés en thérapeutique pour le traitement des troubles de la vigilance, en particulier pour lutter contre les troubles du comportement imputables à des dommages vasculaires cérébraux et à la sclérose cérébrale en gériatrie, ainsi que pour le traitement des absences dues à des traumatismes craniens, et le traitement des états dépressifs.The compounds of the invention, possessing an antianoic activity, can be used in therapy for the treatment of vigilance disorders, in particular for combating behavioral disorders attributable to cerebrovascular damage and cerebral sclerosis in geriatrics, as well as for the treatment of absences due to cranial trauma, and the treatment of depressive states.
L'invention comprend par conséquent, toutes compositions pharmaceutiques renfermant les composés et/ou leurs sels comme principes actifs, en association avec tous excipients appropriés à leur administration, en particulier par voie orale ou parentérale.The invention therefore includes any pharmaceutical compositions containing the compounds and / or their salts as active ingredients, in combination with any excipients suitable for their administration, in particular orally or parenterally.
Les voies d'administration peuvent Btre les voies orale et parentérale
La posologie quotidienne peut aller de 10 à 200 mg. The routes of administration may be the oral and parenteral routes
The daily dosage can range from 10 to 200 mg.
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8021643A FR2491926A1 (en) | 1980-10-10 | 1980-10-10 | Raubasine (ajmalicine or delta-yohimbine) anti-anoxic derivs. - used for treat cerebral vascular damage, cerebral sclerosis, cranial trauma disorders and depressive states |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8021643A FR2491926A1 (en) | 1980-10-10 | 1980-10-10 | Raubasine (ajmalicine or delta-yohimbine) anti-anoxic derivs. - used for treat cerebral vascular damage, cerebral sclerosis, cranial trauma disorders and depressive states |
Publications (2)
Publication Number | Publication Date |
---|---|
FR2491926A1 true FR2491926A1 (en) | 1982-04-16 |
FR2491926B1 FR2491926B1 (en) | 1983-08-19 |
Family
ID=9246725
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
FR8021643A Granted FR2491926A1 (en) | 1980-10-10 | 1980-10-10 | Raubasine (ajmalicine or delta-yohimbine) anti-anoxic derivs. - used for treat cerebral vascular damage, cerebral sclerosis, cranial trauma disorders and depressive states |
Country Status (1)
Country | Link |
---|---|
FR (1) | FR2491926A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5281607A (en) * | 1992-10-08 | 1994-01-25 | New York University | Method of using Alpha 2-Antagonists for the Treatment of Neurodegenerative Diseases |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2442664A1 (en) * | 1978-12-01 | 1980-06-27 | Bbc Brown Boveri & Cie | DUST SEPARATOR FOR ELIMINATING DUST, EVEN FINE, PRESENT IN FLOWS OF GASEOUS FLUIDS |
FR2450825A1 (en) * | 1979-03-09 | 1980-10-03 | Synthelabo | BENZODIAZEPINE DERIVATIVES AND THEIR THERAPEUTIC APPLICATION |
-
1980
- 1980-10-10 FR FR8021643A patent/FR2491926A1/en active Granted
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2442664A1 (en) * | 1978-12-01 | 1980-06-27 | Bbc Brown Boveri & Cie | DUST SEPARATOR FOR ELIMINATING DUST, EVEN FINE, PRESENT IN FLOWS OF GASEOUS FLUIDS |
FR2450825A1 (en) * | 1979-03-09 | 1980-10-03 | Synthelabo | BENZODIAZEPINE DERIVATIVES AND THEIR THERAPEUTIC APPLICATION |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5281607A (en) * | 1992-10-08 | 1994-01-25 | New York University | Method of using Alpha 2-Antagonists for the Treatment of Neurodegenerative Diseases |
Also Published As
Publication number | Publication date |
---|---|
FR2491926B1 (en) | 1983-08-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
FR2534257A1 (en) | NOVEL 6-AMINO 7-HYDROXY 4,5,6,7-TETRAHYDRO-IMIDAZO / 4,5,1-JK / / 1 / BENZAZEPIN-2 (1H) -ONE DERIVATIVES, THEIR SALTS, APPLICATION AS MEDICAMENTS , COMPOSITIONS COMPRISING THEM AND AN INTERMEDIARY | |
EP0307303A1 (en) | 1-[(2-Pyrimidinyl)-aminoalkyl] piperidines, their preparation and their use in therapy | |
WO1997003987A1 (en) | Novel galanthamine derivatives, preparation method therefor, use thereof as drugs, and pharmaceutical compositions containing such derivatives | |
CH645642A5 (en) | D-6-N-PROPYLERGOLINS DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. | |
EP0087378B1 (en) | Oxime-ethers of alkylamino alcohols as medicaments, compounds and process for their preparation | |
FR2584713A1 (en) | NOVEL CARBOXAMIDE INDOLE DERIVATIVES, THEIR SALTS, PROCESS AND PREPARATION INTERMEDIATES, MEDICAMENT APPLICATION AND COMPOSITIONS COMPRISING SAME | |
EP0209770A1 (en) | Eicosatriynoic esters and amides and their use in pharmacy and cosmetics | |
EP1720849B1 (en) | Pyranone derivatives useful for treating cancer | |
FR2551063A1 (en) | New 2,5-dimethylpyrroles, process for preparing them and their therapeutic use | |
FR2491926A1 (en) | Raubasine (ajmalicine or delta-yohimbine) anti-anoxic derivs. - used for treat cerebral vascular damage, cerebral sclerosis, cranial trauma disorders and depressive states | |
EP0043752B1 (en) | Pyranoindole derivative and process for its preparation | |
EP0130882B1 (en) | Bicyclo(3.2.1)octane carboxylic-acid derivatives, processes for their preparation and their therapeutical use | |
EP0082040B1 (en) | 3,7a-diazacyclohepta(j,k)fluorene derivatives, their preparation and therapeutical use | |
FR2758560A1 (en) | NEW DERIVATIVES OF AMINOPHENYLBORONIC ACIDS, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM | |
FR2465733A1 (en) | NOVEL IMIDAZOLYLETHOXYMETHYLIC DERIVATIVES OF 1,3-DIOXOLOQUINOLINES USEFUL AS ANTIBACTERIAL AND ANTIFUNGAL DRUGS, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC COMPOSITIONS AND PHARMACEUTICAL FORMS CONTAINING THEM | |
CA1060020A (en) | Process for the preparation of new dibenzo/b,c/ thiepine derivatives and salts thereof | |
FR2723372A1 (en) | NOVEL STREPTOGRAMIN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM | |
EP1131293A1 (en) | 1-aminoethylquinoline derivatives for treating urinary incontinence | |
BE864450R (en) | ANTHOCYANIDINE-BASED PHARMACEUTICAL COMPOSITIONS, THEIR PREPARATION AND THEIR USE | |
EP1242381A2 (en) | 2-phenyl-quinoline derivatives, preparation method and therapeutic use thereof | |
LU82833A1 (en) | OXAYOHIMBANE-CARBOXYLIC ACID DERIVATIVES | |
FR2581996A1 (en) | NOVEL 6-SUBSTITUTED 6H-DIBENZO (B, D) THIOPYRANES DERIVATIVES USEFULLY IMMUNOMODULATORS AND ANTIVIRALS AND THEIR PREPARATION | |
EP0647221A1 (en) | 1-aryl(4-o-alkoxyphenyl 1-piperazinyl)-2, -3 or -4 alkanols, process for their preparation and use thereof in the preparation of drugs | |
EP0179076A1 (en) | Sulphureous hydantoin derivatives and pharmaceutical compositions containing them. | |
FR2556592A1 (en) | Pharmaceutical compositions containing camphormethylidenecinnamic acid derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
ST | Notification of lapse |