EP0460153A1 - NOUVEAUX $g(b)-CARBOLINES, PROCEDES POUR LEUR FABRICATION ET LEUR UTILISATION DANS DES MEDICAMENTS - Google Patents

NOUVEAUX $g(b)-CARBOLINES, PROCEDES POUR LEUR FABRICATION ET LEUR UTILISATION DANS DES MEDICAMENTS

Info

Publication number
EP0460153A1
EP0460153A1 EP91900736A EP91900736A EP0460153A1 EP 0460153 A1 EP0460153 A1 EP 0460153A1 EP 91900736 A EP91900736 A EP 91900736A EP 91900736 A EP91900736 A EP 91900736A EP 0460153 A1 EP0460153 A1 EP 0460153A1
Authority
EP
European Patent Office
Prior art keywords
carboline
methoxymethyl
alkyl
ethyl acetate
hydrogen
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.)
Withdrawn
Application number
EP91900736A
Other languages
German (de)
English (en)
Inventor
Andreas Dr. Huth
Martin Dr. Krüger
Dieter Rahtz
Dieter Dr. Seidelmann
Ralph Dr. Schmiechen
Lechoslaw Dr. Turski
John Stewart Dr. Andrews
Herbert Hans Dr. Schneider
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP0460153A1 publication Critical patent/EP0460153A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the invention relates to new ß-carbolines, their production and use in drugs.
  • the compounds according to the invention have the general formula I.
  • R A is halogen, -CHR 1 -R 2 , phenyl or OR and can be one to two times and
  • R 2 is hydrogen, C 1-4 alkyl, -OC 1-4 alkyl or an optionally substituted phenyl, benzyl or phenoxy radical and
  • R 5 represents hydrogen, tri-C 1-4 -alkylsilyl, C 1 -4 -alkyl, C 3-7 -cycloalkyl or an optionally substituted phenyl, benzyl or hetaryl radical and
  • B nitrogen or CR 4 and R 4 is hydrogen, C 1-4 alkyl or C 1-4 alkoxy-C 1-2 alkyl and
  • R 3 is -CO-R or -CHOH-R and R represents an optionally substituted mono- or bicyclic aryl or hetaryl radical or a C 3-10 cycloalkyl or bicycloalkyl radical and their isomers and acid addition salts.
  • the substituent R A can be in the A ring in position 5-8, preferably in the 5-, ⁇ - or 7-position.
  • Alkyl contains both straight and branched chain residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl and tert. Butyl.
  • Halogen is to be understood as fluorine, chlorine, bromine and iodine.
  • Cycloalkyl can each represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and 2-methylcyclopropyl, 3-5 carbon atoms being preferred for the substituent R 5 .
  • R 5 is a hetaryl radical, this is 5- or 6-membered and contains 1-2 heteroatoms such as nitrogen, oxygen and / or sulfur.
  • 5- and 6-ring heteroaromatics may be mentioned: pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, thiazole, imidazole.
  • Preferred hetaryl radicals R 5 are nitrogen-containing heterocycles which are optionally substituted with halogen.
  • the substituent of the phenyl, benzyl and hetaryl radical R 5 can be one to three times in any position.
  • Suitable substituents are halogens, nitro, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino and C 1-4 alkoxy carbonyl, in particular fluorine, chlorine and bromine being preferred.
  • Suitable substituents for the phenyl, benzyl and phenoxy radical R 2 are the substituents for aromatics mentioned for R 5 , in particular halogen such as
  • the aryl and hetaryl radical in R 3 can be present as a mono- or bicyclic and
  • 5-12 ring atoms preferably 5-9 ring atoms, contain, for example, phenyl, biphenylyl, naphthyl, indenyl as aryl radical and thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, iso-oxazolyl, thiazolyl, isothiazolyl, Quinolyl, isoquinolyl, benzo [1] thienyl, benzofuryl as a hetaryl radical with 1-2 heteroatoms such as sulfur, oxygen and / or nitrogen.
  • the substituent of the aryl and hetaryl radical R can be one to two times and can be halogen, C 1-4 alkyl, C 1-4 alkoxy, cyano, amino or nitro, where C 1-4 alkyl, C 1-4 Alkoxy and amino are preferred.
  • a bicycloalkyl radical R is understood to mean, for example, bicycloheptyl and bicylooctyl.
  • the compounds of the formula I can be in the form of the diastereomers and mixtures thereof.
  • the physiologically compatible acid addition salts are derived from the known inorganic and organic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid and, for example, alkanesulfonic acids and, for example, alkanesulfonic acids and, for example, alkanesulfonic acids Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and others
  • cycloalkyls having 3-5 carbon atoms and optionally substituted phenyl, biphenyl, naphthyl and thienyl are to be considered as particularly preferred embodiments for R.
  • the compounds of the formula I and their acid addition salts can be used as medicaments and exert antagonistic, inverse agonistic and agonistic effects on the properties known from benzodiazepines.
  • the compounds according to the invention have an extended duration of action.
  • the table below shows that the compounds according to the invention not only have a higher stability towards liver enzymes, but also a better affinity for the benzodiazepine receptors, in particular better have vivo affinity. Affinity is determined by examining the displacement capacity of radioactively labeled flunitrazepam from the benzodiazepine receptors.
  • the ED 50 value represents the dose of a test substance which brings about a reduction in the specific binding of the flunitrazepam to the benzodiazepine receptor in a living brain to 50% of the control value.
  • mice Groups of mice are injected with the test substance at different doses and usually intraperitoneally. After 15 minutes, the 3 H-flunitrazepam is administered intravenously to the mice. After a further 20 minutes, the mice are sacrificed, their forebrain removed and the radioactivity specifically bound to the brain membranes measured by scintillation payment. The ED 50 value is determined from the dose / effect curves,
  • the metabolic stability is determined by incubating a homogenate of liver tissue in physiological saline with the test substance for 0 or 2 hours at 37 ° C. The incubation mixture is then extracted and the content of test substance in the extract is determined by HPLC / fluorimetry. The substance remaining after 2 hours compared to 0 hours is expressed in percent stability. Inhibition of H 3 -BD binding Metabolic stability in vivo Human liver homogenate
  • the compounds according to the invention are further distinguished by anxiolytic and anticonvulsant activity.
  • the compounds are tested in a 4-plate test using the method of Boissier et al Eur. J. Pharmacol. 4, 145-150 (1968).
  • MED minimum, lowest dose
  • a decrease in activity in the 4-plate test without punishment indicates sedative properties.
  • the compounds of the formula I are particularly suitable for the treatment of anxiety accompanied by depression, epilepsy, sleep disorders, spasticity and muscle relaxation during anesthesia and also show amnestic or memory-promoting properties.
  • the compounds according to the invention are brought into the form of a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as water, gelatin, gum arabic, milk sugar, starch, Contains magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc.
  • suitable pharmaceutical, organic or inorganic inert carrier materials such as water, gelatin, gum arabic, milk sugar, starch, Contains magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc.
  • the pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
  • Injection solutions or suspensions in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.
  • Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.
  • Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. They can also be used in liquid form, for example as juice, to which a sweetener may be added.
  • the compounds according to the invention are introduced in a dose unit of 0.05 to 100 mg of active substance in a physiologically compatible carrier.
  • the compounds according to the invention are generally used in a dose of 0.1 to 300 mg / day, preferably 0.1 to 30 mg / day, particularly preferably 1-20 mg / day, for example as anxiolytics analogous to diazepam.
  • R A and B have the above meaning
  • R 9 is hydrogen or a protective group
  • Z is hydrogen, C 1-4 alkoxy or an acid derivative, with a metal-organic compound R-Me
  • a Grignard compound such as R-Mg halogen or a lithium organic compound R-Li is suitable as the organic metal compound.
  • R-Mg halogen or a lithium organic compound R-Li is suitable as the organic metal compound.
  • R-Mg halogen or a lithium organic compound R-Li is suitable as the organic metal compound.
  • Acid derivatives are, for example, carboxamides -NR 7 R 8 , in which R 7
  • C 1-4 alkyl and R 8 represent C 1-4 alkyl or C 1-4 alkoxy or R 7 and R 8 together with the nitrogen atom form an imidazole.
  • the reaction with the organometallic compound can be carried out at temperatures from -70 ° C. to room temperature in aprotic polar solvents such as cyclic and acyclic ethers or hydrocarbons.
  • aprotic polar solvents such as cyclic and acyclic ethers or hydrocarbons.
  • suitable solvents are diethyl ether, tetrahydrofuran, dioxane, toluene, hexane and others.
  • Suitable protective groups R 9 are all customarily used protective groups, such as, for example, alkyl, alkanoyl, aralkyl, arylsulfonyl,
  • Trialkylsilyl such as tert. Butyl-dimethylsilyl, trimethylsilyl and tert.
  • a protective group R 9 or the tri-C 1-4 -alkylsilyloxy group R A is present in the compounds of the formula I, this can be carried out using the customary methods, such as by treatment with bases such as sodium or potassium hydroxide or alcoholate or Acids such as dilute mineral acid, trifluoroacetic acid or tetrabutylammonium fluoride, if necessary when the reaction mixture is worked up, are eliminated at room temperature or elevated temperature.
  • the methods described in EP-237467, EP-A-234173 and EP-A-130140 can be used, for example by using a reactive derivative R 5 X, in which X Halogen, tosylate, mesylate or triflate is reacted in the presence of a base in a polar solvent.
  • R 5 X a reactive derivative
  • X Halogen, tosylate, mesylate or triflate is reacted in the presence of a base in a polar solvent.
  • the compounds of formula IR 3 have the meaning of a -CHOH-R-
  • this can be oxidized to a -CO-R group by optionally in the presence of an organic base such as pyridine, triethylamine with oxalyl chloride or with an oxidizing agent such as manganese dioxide,
  • Oxidation with azodicarboxylic acid esters for example analogously to F.
  • the reaction can be carried out at room temperature or at an elevated temperature up to the boiling point of the reaction mixture in an inert solvent such as chlorinated hydrocarbons, hydrocarbons, acetone, alcohols such as tert. Butanol can be carried out.
  • an inert solvent such as chlorinated hydrocarbons, hydrocarbons, acetone, alcohols such as tert. Butanol can be carried out.
  • the isomer mixtures can be separated into the diastereomers or enantiomers by customary methods such as, for example, crystallization, chromatography or salt formation.
  • a compound of the formula I is dissolved, for example, in a little alcohol and a concentrated solution of the desired acid is added.
  • the 3-formyl derivative of the formula II can be prepared analogously to the methods described in EP-A-218541 and EP-A-305322.
  • the preparation of the 3-carboxylic acid esters and their reactive acid derivatives is described for example in EP-A-54507, EP-A-237467, EP-A-234173, EP-A-137390, EP-A-239667 and EP-A222693.
  • the nitriles are prepared, for example, by the process described in EP-A-234137.
  • Example 2 Analogously to Example 2, the title compound is obtained from 8-phenoxy-5-tosyl-5H-pyrimido [5,4-b] indole-2-carboxylic acid ethyl ester, melting point 251-253 ° C (ethyl acetate).
  • 2-Amino-5-phenoxy-benzonitrile is analogous to that of K. Clarke, W. Richard and R.M. Scrowston, J. Chem. Res. 1980 (2) 833-847 converted synthesis into 3-amino-4-phenoxy-1-tosylindol-2-carbonitrile, which analogously to the process described in EP-A-115248 in 8-phenoxy -5-tosyl-5H-pyrimido [5,4-b] indole-2-carboxylic acid ethyl ester with the melting point 136-139 ° C (ethanol) is transferred.
  • Example 2 Analogously to Example 2, the title compound is obtained from 5-ethoxymethyl-9-tosyl-ßcarbolin-3-carboxylic acid ethyl ester, melting point 195-197 ° C (ethyl acetate).
  • Example 2 Analogously to Example 2, the title compound is obtained from 4,5-dimethyl-9-tosyl- ⁇ -carboline-3-carboxylic acid ethyl ester, melting point 208-209 ° C. (ethyl acetate).
  • the starting compounds are prepared by known esterification and tosylation of 4,5-dimethyl- ⁇ -carboline-3-carboxylic acid.
  • Example 2 Analogously to Example 2, the title compound is obtained from 5-ethoxymethyl-4-methoxymethyl-9-tosyl- ⁇ -carboline-3-carboxylic acid ethyl ester, melting point 180-182 ° C. (ethanol).
  • the starting material is prepared by tosylating the 5-ethoxymethyl-4-methoxymethyl-ß-carboline-3-carboxylic acid ethyl ester known from EP-A-161575, melting point 90-92 ° C. (ethanol).
  • Example 2 Analogously to Example 2, the title compound is obtained from 5- (2-chlorophenoxymethyl) 4-methoxymethyl-9-tosyl- ⁇ -carboline-3-carboxylic acid ethyl ester, melting point 149 ° -152 ° C. (ethanol).

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit des composés de la formule (I), où B est de l'azote ou CR4 et où R3 est CO-R ou -CHOH-R, et où R représente un résidu aryle ou hétaryle mono-ou bicyclique éventuellement substitué, ou bien un résidu C3-10 cycloalkyle ou bicycloalkyle. Les composés de la formule (I) se prêtent particulièrement au traitement de l'angoisse accompagnée de dépressions, d'épilepsie, de troubles du sommeil, de spasticités et de relaxation musculaire pendant l'anesthésie, et présentent aussi des propriétés amnestiques ou stimulant la mémoire.
EP91900736A 1989-12-23 1990-12-19 NOUVEAUX $g(b)-CARBOLINES, PROCEDES POUR LEUR FABRICATION ET LEUR UTILISATION DANS DES MEDICAMENTS Withdrawn EP0460153A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3943225A DE3943225A1 (de) 1989-12-23 1989-12-23 Neue ss-carboline, verfahren zu deren herstellung und deren verwendung in arzneimitteln
DE3943225 1989-12-23

Publications (1)

Publication Number Publication Date
EP0460153A1 true EP0460153A1 (fr) 1991-12-11

Family

ID=6396566

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91900736A Withdrawn EP0460153A1 (fr) 1989-12-23 1990-12-19 NOUVEAUX $g(b)-CARBOLINES, PROCEDES POUR LEUR FABRICATION ET LEUR UTILISATION DANS DES MEDICAMENTS

Country Status (9)

Country Link
US (1) US5254563A (fr)
EP (1) EP0460153A1 (fr)
JP (1) JPH04505928A (fr)
CA (1) CA2050917A1 (fr)
DE (1) DE3943225A1 (fr)
HU (1) HUT59403A (fr)
IE (1) IE904704A1 (fr)
PT (1) PT96351A (fr)
WO (1) WO1991009858A1 (fr)

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4120109A1 (de) * 1991-06-15 1992-12-17 Schering Ag 3-aryl- oder 3-hetaryl-(beta)-carboline, deren herstellung und verwendung in arzneimitteln
DE4130933A1 (de) * 1991-09-13 1993-03-18 Schering Ag Neue (beta)-carbolinderivate, deren herstellung und verwendung in arzneimitteln
DE4330175A1 (de) * 1993-08-31 1995-03-02 Schering Ag Alkoxy-substituierte beta-Carboline
IL115420A0 (en) 1994-09-26 1995-12-31 Zeneca Ltd Aminoheterocyclic derivatives
GB9602166D0 (en) * 1996-02-02 1996-04-03 Zeneca Ltd Aminoheterocyclic derivatives
US6313127B1 (en) 1996-02-02 2001-11-06 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
UA56197C2 (uk) 1996-11-08 2003-05-15 Зенека Лімітед Гетероциклічні похідні
DK0966462T3 (da) 1997-02-13 2003-09-22 Astrazeneca Ab Heterocykliske forbindelser, der er egnede som oxidosqualencyklaseinhibitorer
US6440972B1 (en) 1997-02-13 2002-08-27 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
GB9715895D0 (en) 1997-07-29 1997-10-01 Zeneca Ltd Heterocyclic compounds
GB9716656D0 (en) * 1997-08-07 1997-10-15 Zeneca Ltd Chemical compounds
GB9716657D0 (en) 1997-08-07 1997-10-15 Zeneca Ltd Chemical compounds
GB9803226D0 (en) 1998-02-17 1998-04-08 Zeneca Ltd Chemical compounds
GB9902453D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902459D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902455D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902461D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902452D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902989D0 (en) 1999-02-11 1999-03-31 Zeneca Ltd Heterocyclic derivatives
GB0000625D0 (en) 2000-01-13 2000-03-01 Zeneca Ltd Chemical compounds
US20030045541A1 (en) * 2001-07-23 2003-03-06 Christopher Bruckner GABA-Receptor modulators with NMDA-Antagonistic activity

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57123180A (en) * 1980-12-17 1982-07-31 Schering Ag 3-substituted beta-carboline, manufacture and psychotropic drug containing same
DE3246932A1 (de) * 1982-12-16 1984-06-20 Schering AG, 1000 Berlin und 4709 Bergkamen Substituierte 5h-pyrimido(5,4-b)indole
GB8720125D0 (en) * 1987-08-26 1987-09-30 Roussel Lab Ltd Chemical compounds

Non-Patent Citations (1)

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Title
See references of WO9109858A1 *

Also Published As

Publication number Publication date
PT96351A (pt) 1991-09-30
US5254563A (en) 1993-10-19
JPH04505928A (ja) 1992-10-15
DE3943225A1 (de) 1991-06-27
HU912769D0 (en) 1992-01-28
WO1991009858A1 (fr) 1991-07-11
HUT59403A (en) 1992-05-28
IE904704A1 (en) 1991-07-17
CA2050917A1 (fr) 1991-06-24

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