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WO2002000609A2 - Tetralines 2,6,7-substituees convenant a l'elaboration de medicaments inhibiteurs de la phosphodiesterase iv - Google Patents

Tetralines 2,6,7-substituees convenant a l'elaboration de medicaments inhibiteurs de la phosphodiesterase iv Download PDF

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Publication number
WO2002000609A2
WO2002000609A2 PCT/IT2001/000311 IT0100311W WO0200609A2 WO 2002000609 A2 WO2002000609 A2 WO 2002000609A2 IT 0100311 W IT0100311 W IT 0100311W WO 0200609 A2 WO0200609 A2 WO 0200609A2
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methoxy
cyclopentyloxy
tetrahydro
preparation
group
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WO2002000609A3 (fr
Inventor
Nicola Fanto'
Maria Ornella Tinti
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Sigma Tau Industrie Farmaceutiche Riunite SpA
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Sigma Tau Industrie Farmaceutiche Riunite SpA
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Priority to AU2001270984A priority Critical patent/AU2001270984A1/en
Publication of WO2002000609A2 publication Critical patent/WO2002000609A2/fr
Publication of WO2002000609A3 publication Critical patent/WO2002000609A3/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C265/00—Derivatives of isocyanic acid
    • C07C265/10—Derivatives of isocyanic acid having isocyanate groups bound to carbon atoms of rings other than six-membered aromatic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/32—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/44—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/08—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/34—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/38—Unsaturated compounds containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the invention described herein relates to compounds for use as medicaments, to processes for their preparation, to pharmacological compositions containing them and to their use for the preparation of medicaments, and more particularly for medicaments useful as selective phosphodiesterase IV inhibitors.
  • the phosphodiesterases are a large family of enzymes which act on different substrates over an extensive area of metabolic regulation.
  • the phosphodiesterases are a large family of enzymes which act on different substrates over an extensive area of metabolic regulation.
  • the invention described herein tackles the problem of supplying selective inhibitors of phosphodiesterase IV (briefly, also referred to as PDE IV) .
  • Phosphodiesterase IV inhibitors are also known to be useful agents in the treatment of respiratory tract diseases, particularly as inti-inflammatory agents and bronchodilators.
  • rolipram Reeves et al. Biochem J., 241, 535-541 (1987), US
  • W099/ 15494 as agents useful for the treatment and prevention of septic shock.
  • WO 9704775 describes substituted dihydropyridopyrimidines as selective inhibitors of PDE IV.
  • A is the -NHR7 group, in which R7 is -H, alkanoyl, C1-C4 alkylcarbamoyl, in which the alkyl may be substituted with halogens; arylcarbamoyl; - -NCO;
  • a first preferred group of formula (I) compounds are those in which Ri is halogen and R2 alkoxy or cycloalkoxy; in particular, within this group, a particular preference goes to compounds in which R2 is cyclopentyloxy.
  • a second preferred group of formula (I) compounds are those in which R5 and Re together are the keto group, or the corresponding oxime.
  • a third preferred group of formula (I) compounds are those in which A is the -COORs, -NCO or -CONHOH group.
  • the following compounds are preferred:
  • an appropriate starting compound will be selected from the group consisting of benzene 1,2, substituted with the groups Ri and R2 indicated above, such as 2- halophenol (2-chlorophenol, 2-fluorophenol, 2-bromophenol, 2- iodophenol), ethers with C1-C4 alkyl or C5-C6 cycloalkyl of 2- alkoxyphenol (2-chlorophenol methyl ether, 2-fluorophenol methyl ether, 2-bromophenol methyl ether, 2-iodophenol methyl ether and higher ethers). These compounds are commercially available or can be prepared with methods known in the literature.
  • an appropriate starting compound will be selected from the group consisting of benzene 1,2, substituted with the groups Ri and R2 indicated above, such as 2,3- dimethoxybenzene, 2,3-diethoxybenzene, 2,3-dipropoxybenzene, 2,3- dibutoxybenzene, and the branched isomeric analogues, or 2,3- dicyclopentyloxybenzene, 2,3-dicyclohexyloxybenzene.
  • Starting compounds carrying different Ri and R2 groups are also envisaged. These compounds are commercially available or can be prepared with known methods in the literature.
  • esters of glutaric acid can be used as envisaged in the definition of Rs, alkyl with 1 to 4 carbon atoms, or, the keto group in 4- on the tetraline ring can be conserved up until the end compound.
  • the starting compounds are commercially available or can be prepared with the methods known in the literature.
  • Aspartic acid (100 g: 0.75 mol) is suspended in trifluoroacetic acid (300 ml) under mechanical stirring and cooled with an ice and salt bath; trifluoroacetic anhydride is added drop-wise (300 ml: 2.16 mol), adjusting the addition in such a way as not to let the temperature rise above 10°C.
  • the suspension is left to stir vigorously for half an hour at a temperature below 10°C after which the temperature is allowed to rise slowly.
  • the suspension is reacted for 2 hours at 45°C and for one night at room temperature. Extraction is done with acetone (300 ml) with cooling to solubilise the mass which is of very firm consistency and then the solution is concentrated to dryness.
  • the solid obtained is washed twice with 500 cc of n-hexane and again with 1 litre of n- hexane/ ethyl ether at a ratio of 4: 1, triturating and vacuum filtering. 135 g of product are obtained which can be used as is if the analyses are compliant. Crystallisation by n-hexane/ EtO Ac is performed obtaining 119 g of product which is vacuum dried thoroughly at 40°C. Yield 75%.
  • N-trifluoroaceryl aspartic anhyrdride (1) (58 g: 0.275 mol) is suspended in 100 ml of anhydrous CH2CI2; 2-fluoroanisol (77 ml; 0.68 mol) is then added at room temperature and in a nitrogen atmosphere with mechanical stirring. The temperature is then brought down to +10°C with an ice bath and A1C1 3 (82 g, 0.616 mol) is added in two portions. The cooling is removed and the suspension is left to reach room temperature. The reaction is left under mechanical stirring at room temperature for 2 days. After approximately 5 hours, when the reaction has taken on a red colour, and has started to become less fluid, another 100 ml of CH2CI2 are added.
  • the trifluoroacetic acid is completely eliminated by vacuum evaporation at the lowest possible temperature; the residual oil is cooled with an ice and salt bath and then treated under stirring in a beaker with a saturated solution of NaHCO ⁇ and then with solid NaHC ⁇ 3, under vigorous stirring, adding ether from time to time to avoid excessive frothing.
  • the aqueous phase is washed with ethyl ether and carefully acidified cold with HCl 6N to pH 3.
  • the product precipitates and is then extracted several times with CH2CI2.
  • the organic extracts are gathered, washed with little water, dried on anhydrous Na2S04 and then vacuum dried.
  • the solid is crystallised with AcOEt/ isopropyl ether (220 ml-300 ml) obtaining 16 g of filtered and dried solid; the moter liquors are concentrated to dryness and crystallised in turn by the same solvent (80 ml- 130 ml), yielding 6 g of solid which, when filtered and dried, is added to the previous solid, obtaining 22 g of product. Yield 67%. M.P.
  • the reaction mixture is heated to reflux temperature for 16 hours until the reaction is complete and then filtered, washing the solid with AcOEt and n- hexane; the organic solutions are washed several times with water, with a saturated solution of K2C0 3 and again with water until neutral pH is obtained.
  • the organic solution is anhy drifted with anhydrous sodium sulphate and concentrated to dryness, obtaining an orange-coloured oil weighing 29 g after oil-pump drying, which is used as is, in view of its considerable purity. Yield 73%.
  • the mixture is reacted for 1.5 hours at a 0°C, whereupon 100 ml of cold water are added to the suspension and extraction is done several times with toluene, anhydrifying the organic phase on anhydrous sodium sulphate.
  • the anhydrous solution is added to 50 ml of previously heated toluene and heated further at 105°C for 1.5 hours.
  • the solution is dried, obtaining a dense oily crude product which, after oil-pump drying, weighs 6 g. This crude product is pure enough to be used as is in the next reaction. Yield 87%.
  • the solution is concentrated to dryness, then added with 80 ml of water, acidifying to pH 3 with HCl 6N, cooling and then extracting the aqueous solution several times.
  • the organic phase is anhydified on anhydrous sodium sulphate and concentrated to dryness, obtaining a solid which, when crystallised by n-hexane/ EtOAc gives 2.3 g of product. Yield 73%.
  • PDE IV phosphodiesterase IV
  • Assays conducted with standard processes, e.g. as described by Cortij et al., Br. J. Pharmacol. 108:562, 1993 or Nicholsen CD et al., Trends Pharmacol. Sci. 12: 19, 1991 have yielded the following results for compounds figuring among the examples envisaged within the framework of the invention described herein.
  • N.C. means value not calculable because of no inhibition at the highest test concentration, however it means low affinity for rolipram receptor.
  • a compound exhibits H/L IC50 ratio of about 0.1 or greater calculated as the ratio of the IC50 (H) for high affinity rolipram binding form (HPDE4) divided by the IC50 (L) for the form which binds rolipram with low affinity (LPDE4), it will have an acceptable therapeutic index for treating asthma or chronic obstructive pulmonary disease (COPD), minimizing side effects tipical of phosphodiesterase IV inhibitors as rolipram.
  • HPDE4 high affinity rolipram binding form
  • LPDE4 chronic obstructive pulmonary disease
  • the compounds according to the invention described herein are useful as medicaments, and particularly as phosphodiesterase IV inhibitors.
  • the compounds according to the invention can therefore be used in the preparation of medicaments with phosphodiesterase IV inhibitory activity, particularly for the treatment of asthma or for the treatment of chronic obstructive pulmonary disease.
  • the compounds according to the invention also exert an inhibitory action on the release of TNF (Tumor Necrosis Factor) induced by bacterial LPS (lipopolysaccharides) .
  • TNF Tumor Necrosis Factor
  • LPS lipopolysaccharides
  • the compounds according to the invention are useful as medicaments, particularly for the treatment and prevention of septic shock.
  • compositions are conventionally known and contain a therapeutically effective amount of active ingredient in mixtures with pharmaceutically acceptable excipients and/ or vehicles.
  • the subject matter of the invention described herein comprises pharmaceutical compositions containing as their active ingredient at least one formula (I) compound, either alone or in combination with one or more formula (I) compounds.
  • the active ingredient according to the invention described herein will be in a mixture with appropriate vehicles and/ or excipients commonly used in pharmacy, such as, for example, those described in "Remington's Pharmaceutical Sciences Handbook", latest edition.
  • the compositions according to the invention described herein will contain a therapeutically effective amount of the active ingredient.
  • doses will be decided by the expert in the field, e.g. by the clinician or primary care physician according to the type of disease to be treated and the patient's condition, or concomitantly with the administration of other active ingredients. By way of an example, doses ranging from 0.1 to 100 mg/kg may be indicated.
  • compositions are those that permit oral or parenteral, intravenous, intramuscular, subcutaneous, and transdermal administration as well as administration by nasal or oral spray.
  • Pharmaceutical compositions suitable for the purpose are tablets, soft or rigid capsules, powders, solutions, suspensions, syrups, and solid forms for extempore liquid preparations.
  • Compositions for parenteral administration include, for example, all the intramuscular, intravenous and subcutaneous injectable forms and those which can be administered in the form of solutions, suspensions, or emulsions. We should also mention the liposomal formulations.
  • compositions also include forms entailing the controlled release of the active ingredient, whether in oral administration, as tablets coated with various layers, microencapsulated powders, complexes with cyclodextrin, and depot forms, e.g. of the subcutaneous type, or as depot injections and implants.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des composés représentés par la formule générale (I) dans laquelle les groupes sont tels que définis dans la description. L'invention concerne également des procédés pour leur élaboration et leur utilisation comme médicaments, plus particulièrement pour l'élaboration de médicaments inhibiteurs de la phosphodiestérase IV.
PCT/IT2001/000311 2000-06-23 2001-06-15 Tetralines 2,6,7-substituees convenant a l'elaboration de medicaments inhibiteurs de la phosphodiesterase iv Ceased WO2002000609A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001270984A AU2001270984A1 (en) 2000-06-23 2001-06-15 2,6,7-substituted tetralines useful for the preparation of medicaments with phosphodiesterase iv inhibitory activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2000RM000342A IT1317050B1 (it) 2000-06-23 2000-06-23 Tetraline 2,6,7-sostituite utili per la preparazione di un medicamentoad attivita' inibitrice della fosfodiesterasi iv.
ITRM2000A000342 2000-06-23

Publications (2)

Publication Number Publication Date
WO2002000609A2 true WO2002000609A2 (fr) 2002-01-03
WO2002000609A3 WO2002000609A3 (fr) 2002-05-02

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PCT/IT2001/000311 Ceased WO2002000609A2 (fr) 2000-06-23 2001-06-15 Tetralines 2,6,7-substituees convenant a l'elaboration de medicaments inhibiteurs de la phosphodiesterase iv

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AU (1) AU2001270984A1 (fr)
IT (1) IT1317050B1 (fr)
WO (1) WO2002000609A2 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1290910B1 (it) * 1997-02-03 1998-12-14 Sigma Tau Ind Farmaceuti 2-amminotetralina otticamente attiva, procedimento per la sua preparazione e composizioni farmaceutiche che la contengono, attive
IT1294931B1 (it) * 1997-09-22 1999-04-23 Sigma Tau Ind Farmaceuti Derivati della 2-amminotetralina procedimento per la loro preparazione e composizioni farmaceutiche che li contengono, attive nella

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IT1317050B1 (it) 2003-05-26
AU2001270984A1 (en) 2002-01-08
ITRM20000342A1 (it) 2001-12-23
ITRM20000342A0 (it) 2000-06-23
WO2002000609A3 (fr) 2002-05-02

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