EP1109783A2 - Inhibiteurs d'absorption de gaba a structure pyrrolidinique - Google Patents

Inhibiteurs d'absorption de gaba a structure pyrrolidinique

Info

Publication number
EP1109783A2
EP1109783A2 EP99968664A EP99968664A EP1109783A2 EP 1109783 A2 EP1109783 A2 EP 1109783A2 EP 99968664 A EP99968664 A EP 99968664A EP 99968664 A EP99968664 A EP 99968664A EP 1109783 A2 EP1109783 A2 EP 1109783A2
Authority
EP
European Patent Office
Prior art keywords
mmol
optionally substituted
alkyl
groups
compounds according
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Withdrawn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
EP99968664A
Other languages
German (de)
English (en)
Inventor
Klaus Wanner
Günther FÜLEP
Georg HÖFNER
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.)
Turicum Drug Development AG
Original Assignee
BDD Berolina Drug Development AB
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 BDD Berolina Drug Development AB filed Critical BDD Berolina Drug Development AB
Publication of EP1109783A2 publication Critical patent/EP1109783A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • 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
    • 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

Definitions

  • the present invention relates to GABA uptake inhibitors with a pyrrolidine structure.
  • the present invention further relates to pharmaceutical compositions containing such compounds and the use of these compounds for the treatment of diseases of the central nervous system (CNS) in which GABA uptake inhibitors play a role, for example epilepsy and Huntington's chorea.
  • CNS central nervous system
  • epilepsy is still one of the most common diseases of the brain. Due to the wide variety of seizure types and a still lacking aetiological understanding, the therapeutic approaches are still limited to controlling symptoms, such as that Suppression of seizures.
  • the list of anti-epileptics was expanded to include the benzodiazepine group. Examples include diazepam and clonazepam.
  • GABA A receptor is an ion channel protein that is composed of different subunits.
  • GABA transport protein A high-affinity GABA transport system was discovered in rat cortex sections in 1968, which ensures the uptake of neurotransmitters released into the synaptic cleft and thus the termination of the neurotransmitter signal. Such a GABA transport protein was first isolated in 1978.
  • GABA uptake proteins with 0.1% of the membrane proteins occur relatively frequently in the nervous system.
  • four different representatives of neurotransmitter transport proteins have been detected by cloning and heterologous expression.
  • GAT-1 The first member of this family to clone from cDNA was designated GAT-1. This protein is also the first neurotransmitter transporter that has been successfully cloned and expressed. A short time later, human GAT-1 was cloned.
  • GAT-2 transport proteins
  • GAT-3 transport proteins
  • BGT-1 transport system for betaine and GABA
  • nipecotinic acid and guvacin As early as 1975, the inhibitory effect of nipecotinic acid and guvacin on the reuptake of GABA was discovered in studies with nipecotinic acid, guvacin and arecaidin, active ingredients from Bethelnut (Areca catechu). With the knowledge of the relationships in GABAergic neurotransmission, new strategies in the treatment of epilepsy emerged. For example, it is possible to increase the neuronal GABA transmission by direct GABA mimetics. GABA itself is not suitable for this because it cannot cross the blood-brain barrier. One problem with direct GABA mimetics is that tolerance can develop through them.
  • GABAergic neurotransmission in a non-specific way in general in the GABAergic synapses and not only where signals arrive.
  • Those mechanisms of action represent a particularly useful therapeutic approach that only increase GABAergic neurotransmission when the transmitter is released. This can be achieved on the one hand by inhibiting the degradation of the transmitter and on the other hand by inhibiting its resumption.
  • the development of appropriate inhibitors for GABA reuptake began with the compounds nipecotinic acid and guvacin mentioned above. However, like GABA, these cannot or only very barely cross the blood-brain barrier.
  • the object of the present invention was to provide new GABA uptake inhibitors and in particular to provide GABA uptake inhibitors with high selectivity for GAT-3 (or at least high affinity for GAT-1).
  • the above object is achieved according to the invention by the compounds of the general formula (I)
  • a 2 stands for (-CR 10 R 11 -) m , where R 10 and R 11 are independently selected from H, i.e. 2-alkyl and halogen; where for im> 2 the groups R 10 and R 11 can be different in each grouping, there can be a grouping - O- or -S- between two neighboring groups and two groups of R 10 and R 11 each on adjacent C atoms can be replaced by a CC bond; and wherein one of R 10 and R 11 may be combined with one of R 1 to R 9 to form a 5- to 7-membered ring structure; and m is 1, 2, 3 or 4;
  • the present invention also relates to pharmaceutical compositions which contain at least one pharmaceutically acceptable carrier or excipient and at least one compound of the general formula (I).
  • the present invention is also directed to the use of the compounds of general formula (I) for the manufacture of a medicament for the treatment of diseases in which the enhancement of GABAergic neurotransmission is beneficial, particularly epilepsy, Huntington's disease and related disorders of the CNS.
  • the compounds according to the invention can also be used successfully as anticonvulsants, sedatives, anxiolytics and antidepressants.
  • the present invention is explained in more detail below on the basis of preferred embodiments thereof.
  • -6- alkyl, C 2-6 alkenyl and C 2-6 alkynyl is intended to represent groups which are unsubstituted or (preferably one or two) substituents which are in particular selected from OH, halogen (in particular F, Cl, Br and particularly preferably F), CN, NO 2 and OR 12 .
  • the substituents can also (and additionally) be (optionally substituted) aryl or heteroaryl radicals (as defined in more detail below).
  • Methyl, ethyl, propyl, CF 3 , CH 2 OCH 3 , CH 2 OH, benzyl and phenethyl can be mentioned as concrete examples of the radicals R 1 to R 7 just discussed.
  • Optionally substituted aryl or heteroaryl includes aryl groups preferably having 6 to 12 carbon atoms and heteroaryl radicals having 5 to 12 ring members, of which up to three can be heteroatoms (generally selected from N, O and S). These aryl or heteroaryl radicals can be unsubstituted or (preferably with one to three substituents). Preferred examples of such substituents are C -3 alkyl, C 2- alkenyl, OH, halogen (in particular F, Cl, Br), CN, NO 2 , OR 12 and NR 13 R 14 .
  • phenyl, thienyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyranyl and corresponding radicals can be mentioned, which have one to three (preferably one) substituent from the group methyl, ethyl, CF 3 , methoxy , Ethoxy, F, Cl, CN, NH 2 , dimethylamino and diethylamino.
  • R 1 to R 7 is halogen
  • this halogen is preferably fluorine or chlorine, particularly preferably fluorine.
  • R 1 , R 2 and R 7 are preferably not halogen, OR 12 , SR 12 and NR 13 R 14 , since in these cases there is the possibility of enamine formation.
  • R 12 is preferably C -3 alkyl, in particular methyl and ethyl.
  • R 13 and R 14 are preferably identical and are preferably methyl and Ethyl. However, R 13 and R 14 can also form an alkylene group, which would result, for example, in a pyrrolidinyl or piperidinyl radical.
  • R 1 to R 6 are independently selected from H, optionally substituted C -3 alkyl, halogen, OH, CN, optionally substituted phenyl and optionally substituted heteroaryi with five to ten ring members and one or two selected from O, N and S heteroatoms, and in particular from hydrogen, C ⁇ -3 alkyl and phenyl.
  • R 7 preferably represents H. In general, it is preferred if no more than two and in particular no more than one radical from R 1 to R 7 are different from H. It can be particularly advantageous if R 1 to R 7 are all hydrogen.
  • R 1 to R 7 can also be combined to form a 3- to 6-membered ring system (preferably a 5- or 6-membered ring system), which can also contain one or more (preferably one or two) heteroatoms.
  • the heteroatoms are preferably O, N or S.
  • oxo O
  • the substituents which are optionally present on the alkylidene group are preferably those which have been given above as examples of substituents on alkyl, alkenyl and alkynyl radicals R 1 to R 7 .
  • R 1 to R 7 which are located on adjacent C atoms, can also be replaced by a CC bond. This leads to the presence of double or triple bonds in the ring system. In this context, a double bond between the 3 and 4 positions of the pyrrolidine skeleton is preferred.
  • a pyrrole structure is also worth mentioning in this context.
  • a 1 is a combination of (-CR 8 R 9 -) n and (optionally substituted) C 3-6 - cycloalkylene, this should mean that A 1 in particular alkylene-cycloalkylene, cycloalkylene-alkylene and alkylene-cycloalkylene-alkylene can represent.
  • a 1 is preferably (-CR 8 R 9 -) n .
  • Particularly preferred meanings of R 8 and R 9 are H and C -3 alkyl, especially methyl.
  • N has in particular the value 0.1 or 2, 1 or 2 being preferred.
  • a 1 represents or includes optionally substituted C 3-6 cycloalkylene
  • preferred examples of the cycloalkylene group are cyclopropylene, cyclopentylene and cyclohexylene. Any substituents present are preferably selected from C -3 alkyl, halogen (eg F or Cl) and OH. However, the cycloalkylene radical preferably does not have any substituents.
  • a 1 stands for (-CR 8 R 9 -) n or comprises this, for n> 2 R 8 and R 9 both CR 8 R 9 and each group can be different.
  • two groups of R 8 and R 9 on adjacent C atoms can also be replaced by a CC bond (which can lead, for example, to a derivative of acrylic acid) and there can be CR 8 between two adjacent groups R 9 is a -O- or -CO- group, although this is not preferred.
  • one of R 8 and R 9 (preferably located on a carbon atom directly attached to the ring) can be combined with one of R 1 to R 7 (preferably R 5 , R 6 or R 7 ) to form a 5- to 7-membered ring structure be combined.
  • This ring structure can be saturated or unsaturated and also contain one or more heteroatoms, preferably selected from O, N and S.
  • X stands for COOM or a group which can be converted into COOM under physiological conditions.
  • the latter groups include, for example, esters, nitrile and salts.
  • M is preferably hydrogen and corresponding cations of sodium, potassium, calcium and magnesium and ammonium. H and Na are even more preferred as meanings for M, with the most preferred meaning for M being hydrogen.
  • a 2 in the above general formula (I) stands for (-CR 10 R 11 -) m, where R 10 and R 11 are preferably H, methyl, ethyl and halogen (in particular F or Cl).
  • R 10 and R 11 are preferably H, methyl, ethyl and halogen (in particular F or Cl).
  • R 10 and R 11 are preferably H, methyl, ethyl and halogen (in particular F or Cl).
  • R 10 and R 11 are preferably H, methyl, ethyl and halogen (in particular F or Cl).
  • R 10 and R 11 are preferably H, methyl, ethyl and halogen (in particular F or Cl).
  • R 10 and R 11 are preferably H, methyl, ethyl and halogen (in particular F or Cl).
  • m preferably has the value 2 or 3, 2 being particularly preferred. If m> 2, the groups R 10 and R 11 can be different both from one another and from each group CR 10 R 11
  • two adjacent groups CR 10 R 11 can be separated by a group -O- or -S- and two groups of R 10 and R 11 on adjacent C atoms can be replaced by a CC bond, which leads to a double (or triple) bond.
  • the C atom adjacent to the N atom should be free of structural elements which (can) result in an enamine or iminium ion structure.
  • one of R 10 and R 11 can be combined with one of R 1 to R 9 (preferably one of R 1 , R 2 , R 7 , R 8 and R 9 ) combined to form a 5- to 7-membered ring structure, which ring structure may be saturated or unsaturated and may also contain one or more heteroatoms selected from O, N and S, in addition to the ring nitrogen atom.
  • Y are preferably identical. Further preferred meanings for Y are optionally substituted phenyl and optionally substituted thienyl, furanyl and pyrrolyl. Optionally substituted phenyl is particularly preferred. If substituents are present, their number preferably does not exceed 3 and in particular 2, with (only) one substituent being more preferred. Preferred substituents are selected from C 1-3 alkoxy, C -3 alkyl, halogen, OH, NO 2 , CN and NR 13 R 14 . Specific examples of such substituents are methoxy, ethoxy, methyl, ethyl, F, Cl, NH 2 , dimethylamino and diethylamino. A particularly preferred substituent is C -3 alkoxy, especially methoxy. In the case of a phenyl ring, this grouping is preferably in the 2- and / or 4-position, more preferably in the 4-position.
  • the two groups Y are also preferably identical. Further preferred meanings for Y in this case are optionally substituted phenyl or optionally substituted heteroaryl with 5 or 6 Ring members and one or two heteroatoms selected from O, N and S. With regard to the substituents which may be present, reference may be made to the above statements regarding groups Y. When Y is phenyl, the phenyl ring preferably has no substituents. If Y is heteroaryl, Y is preferably optionally substituted thienyl, in particular 3-methyl-2-thienyl.
  • R 15 is preferably H or methyl, more preferably H.
  • R 1 to R 7 hydrogen
  • a 2 -CH 2 CH 2 -;
  • the present invention also includes the individual isomers (enantiomers, diastereomers, optionally cis / trans isomers) of the compounds of the general formula (I) according to the invention.
  • the carbon atom bearing R 7 and A 1 -X is a chiral center, so that the compounds according to the invention are at least present as enantiomers.
  • the present invention is intended to include both the individual enantiomers and racemates of these compounds.
  • the compounds according to the invention have a remarkably high selectivity towards GAT-3 and / or GAT-1 and can accordingly be used for the treatment of disease states in which these transport proteins play a role. Epilepsy and Huntington's disease should be mentioned in this context.
  • the compounds according to the invention and the precursors thereof can be prepared by conventional processes described in the literature or in analogy to such processes. Some of these methods are briefly outlined below. Individual isomers (enantiomers) can be prepared in addition to the usual separation (e.g. by racemate resolution) using processes that use chiral auxiliaries in the preparation. Examples of such methods are also briefly outlined below.
  • Compound rac-3 is also accessible by catalytic hydrogenation of 4 with Pt-C as a catalyst according to the following procedure: Clemo, Melrose, J. Chem. Soc, 1942, 424
  • the compound rac-9 can be synthesized from pyrrole-2-carbaldehyde 5 using the three-step procedure shown in Scheme 2.
  • the condensation product 7 is obtained by reaction of 5 with 6 according to the procedure of Ch. Robinson, L. J. Wiseman, J. Leonhard, C. D. Slater, Tetrahedron, 1989, 45, 4103-4112. Subsequent catalytic hydrogenation, ester hydrolysis and decarboxylation according to the instructions of Clemo et al., J. Chem. Soc, 1950, 1140 leads to rac-9.
  • N-substituted amino acids rac-12 can be synthesized analogously to known processes starting from the amino acid esters rac-10 by alkylation with a suitable electrophile and subsequent ester hydrolysis KE Andersen et al, J Med Chem 1993, 36, 1716-1725 TGM Dhar et al, J Med Chem 1994, 37, 2334-2342
  • Melting points Melting point apparatus according to Dr. Tottoli (Büchi company, No. 512). The melting points were not corrected.
  • Optical rotations Polarimeter 241 MC (from Perkin Elmer).
  • IR spectra FT-IR spectrometer 1600 and Paragon 1000 (from Perkin Elmer). The spectra were recorded as KBr pellets or as a film between NaCl plates.
  • NMR spectra JNMR-GX 400 (Jeol, 400 MHz), TMS as internal standard. The coupling constants were specified with an accuracy of 0.5 Hz. The spectra were post-processed with NUTS, 2D version 4.35, Acora NMR, 1994.
  • Mass spectra Mass spectra: Mass Spectrometer 5989 A with 59980 B Particle Beam LC / MS Interface (Hewlett Packard).
  • Analytical HPLC Chromatography pumps L-6200 Intelligent-Pump and L-6000 (Merck-Hitachi), UV-VIS detectors L-4000 and L-7400 (242 and 254 nm, Merck-Hitachi), integrators D -7500 and D-2500 (Merck-Hitachi), columns: LiChroCart ® cartridge system (Merck):
  • LiChrospher ® Si 60 (5 ⁇ m, 250 x 4 mm with guard column 4 x 4 mm)
  • LiChrosorb ® Si 60 (5 ⁇ m, 250 x 4 mm with guard column 4 4 mm).
  • Reagents and Solvents All reagents were of commercial quality. Dried and distilled solvents were used for the reactions. For Chromatographic purposes were distilled solvents which were additionally degassed for HPLC.
  • HCl gas was introduced into anhydrous CH 2 C1 2 (1 ml 0.1 mmol 14) over a period of 20 min. Then, with vigorous stirring, enamide 14, dissolved in CH 2 C1 2 (0.5 ml each 0.1 mmol), was slowly added dropwise. The introduction of gaseous HCl was not interrupted and continued for another 10-20 minutes. Excess HCl gas was then removed in a high vacuum at -78 ° for 1 h. A solution of the respective organometallic reagent was then added dropwise to the reaction mixture obtained. After the specified reaction time, hydrolysis (H 2 O) took place at -78 °. After separation of the Phases, the aqueous phase was extracted four times with CH 2 C1 2 , the organic phases with sat.
  • Electrophilic amidoalkylation, general working instructions: 0.158 g (0.6 mmol) 14, 6.6 ml ( 4 eq.)
  • the aqueous phase was i. Vak. concentrated and brought to dryness under high vacuum.
  • N-alkylation of the pyrrolidinylalkane carboxylic acid alkyl esters General procedure A: 179 mg (10 mmol) (S) -r> rxOlidin-2-ylacetic acid methyl ester hydrochloride (S-19-HC1, see preparation example 5), 16.6 mg (0.1 mmol) potassium iodide, 276 mg (2.0 mmol ) Potassium carbonate, 327 mg (1.0 mmol) 4,4-bis (3-methyl-2-thienyl) but-3-en-1-yl bromide. Response time: 46 h.
  • the reaction mixture was aqueous in a two-phase system consisting of 10 ml dichloromethane, 15 ml water and 3.7 ml Poured potassium hydroxide solution.

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

Abstract

L'invention concerne des composés de la formule générale (I) dans laquelle R?1 à R7, A1, A2¿, X et Z ont la signification mentionnée dans la description. Ces composés s'utilisent comme inhibiteurs d'absorption de GABA pour traiter des affections telles que par exemple l'épilepsie.
EP99968664A 1998-09-05 1999-09-03 Inhibiteurs d'absorption de gaba a structure pyrrolidinique Withdrawn EP1109783A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19840611A DE19840611A1 (de) 1998-09-05 1998-09-05 GABA-uptake-Inhibitoren mit Pyrrolidinstruktur
DE19840611 1998-09-05
PCT/EP1999/006486 WO2000014064A2 (fr) 1998-09-05 1999-09-03 Inhibiteurs d'absorption de gaba a structure pyrrolidinique

Publications (1)

Publication Number Publication Date
EP1109783A2 true EP1109783A2 (fr) 2001-06-27

Family

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EP99968664A Withdrawn EP1109783A2 (fr) 1998-09-05 1999-09-03 Inhibiteurs d'absorption de gaba a structure pyrrolidinique

Country Status (6)

Country Link
EP (1) EP1109783A2 (fr)
JP (1) JP2002524443A (fr)
AU (1) AU5972699A (fr)
CA (1) CA2343531A1 (fr)
DE (1) DE19840611A1 (fr)
WO (1) WO2000014064A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7355042B2 (en) 2001-10-16 2008-04-08 Hypnion, Inc. Treatment of CNS disorders using CNS target modulators
US7189757B2 (en) 2001-10-16 2007-03-13 Hypnion, Inc. Treatment of sleep disorders using CNS target modulators
WO2003032912A2 (fr) 2001-10-16 2003-04-24 Hypnion, Inc. Traitement de troubles du systeme nerveux central (snc) a l'aide de modulateurs de cible snc
AU2008258599B2 (en) * 2007-06-05 2013-06-13 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Disubstituted phenylpyrrolidines as modulators of cortical catecholaminergic neurotransmission

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4383999A (en) * 1981-05-26 1983-05-17 Smithkline Beckman Corporation Inhibition of GABA uptake by N-substituted azaheterocyclic carboxylic acids and their esters
US4514414A (en) * 1982-10-25 1985-04-30 Smithkline Beckman Corporation N-Substituted pyrrolidineacetic acids and their esters
GB8320704D0 (en) * 1983-08-01 1983-09-01 Wellcome Found Chemotherapeutic agents
US4610995A (en) * 1984-07-27 1986-09-09 Coker Geoffrey G Certain 1,1-diaryl-propenyl-3-(1-pyrrolidino-2-carboxylic acids, derivatives thereof and their anti-histaminic properties
DK704488D0 (da) * 1988-12-19 1988-12-19 Novo Industri As Nye n-substituerede azaheterocykliske carboxylsyrer
DK288385D0 (da) * 1985-06-26 1985-06-26 Novo Industri As Aminosyrederivater
US4910312A (en) * 1985-11-08 1990-03-20 Warner-Lambert Company Various N-substituted 3-piperidine carboxylic acids or N-substituted 3-pyridinecarboxylic acids and derivatives thereof
DE3787657T2 (de) * 1986-01-07 1994-02-03 Novo Ind A S Bagsvaerd Aminosäure-Derivate.
SK285854B6 (sk) * 1996-05-31 2007-09-06 Allelix Neuroscience Inc. Substituovaný amín, spôsoby jeho prípravy a použitie, farmaceutický prostriedok a jeho použitie

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0014064A2 *

Also Published As

Publication number Publication date
JP2002524443A (ja) 2002-08-06
CA2343531A1 (fr) 2000-03-16
AU5972699A (en) 2000-03-27
WO2000014064A3 (fr) 2000-07-20
DE19840611A1 (de) 2000-03-09
WO2000014064A2 (fr) 2000-03-16

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