EP1161412A1 - Composes d'arylation de recepteurs nucleaires - Google Patents

Composes d'arylation de recepteurs nucleaires

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Publication number
EP1161412A1
EP1161412A1 EP00916297A EP00916297A EP1161412A1 EP 1161412 A1 EP1161412 A1 EP 1161412A1 EP 00916297 A EP00916297 A EP 00916297A EP 00916297 A EP00916297 A EP 00916297A EP 1161412 A1 EP1161412 A1 EP 1161412A1
Authority
EP
European Patent Office
Prior art keywords
compound
receptor
nitro
benzamide
chloro
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Withdrawn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
EP00916297A
Other languages
German (de)
English (en)
Inventor
Steven Gerard Glaxo Wellcome Inc. BLANCHARD
Jeffery Edmund Glaxo Wellcome Inc. COBB
Jon Loren Glaxo Wellcome Inc. COLLINS
Timothy Mark Glaxo Wellcome Inc. WILLSON
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.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
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 Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1161412A1 publication Critical patent/EP1161412A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/60—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members
    • C07C2603/62—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members containing three- or four-membered rings
    • C07C2603/64—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members containing three- or four-membered rings having a tricyclo[2.2.1.0(2,6)]heptstructure

Definitions

  • the present invention relates to compounds that bind to and arylate nuclear receptors.
  • the present invention relates to methods for associating a particular disease or condition with a particular nuclear receptor.
  • Nuclear receptors are transcription factors belonging to the steroid/retinoid receptor superfamily that are activated or deactivated by small lipophilic hormones. See, for example Mangelsdorf, D. J. et al., Cell, (1995), 83, 835-839.
  • the Peroxisome Proliferator Activated Receptors (PPARs) are orphan members of the nuclear receptor superfamily. See, for example, Willson, T. M. and Wahli, W., Curr. Opin. Chem. Biol., (1997), Vol. 1 , pp 235- 241.
  • PPAR-alpha Three mammalian PPARs have been identified which are termed PPAR-alpha, PPAR-gamma, and PPAR-delta.
  • PPARs regulate expression of target genes by binding to DNA response elements as heterodimers with the retinoid X receptor.
  • DNA response elements PPRE
  • PPRE DNA response elements
  • the biological role of the PPARs in the regulation of lipid metabolism and storage has been recently reviewed. See, for example, Spiegelman, B. M., Diabetes, (1998), Vol. 47, pp 507-514, Schoonjans, K., Martin, G., Staels, B., and Auwerx, J., Curr. Opin.
  • Essential dietary fatty acids and certain of their eicosanoid metabolites are naturally-occurring hormones for the PPAR receptors. These hormones can promote adipogenesis through activation of the PPAR-gamma receptor. See, for example, Kliewer, S. A., et al., Proc. Natl. Acad. Sci. USA, (1997), Vol. 94, pp 4318-4323, and Kliewer, S. A., et al., Cell, (1995), Vol. 83, pp 813-
  • Molecules that inhibit the adipogenic effects of endogenous PPAR- gamma hormones may be useful in the treatment of diseases caused by increased fat accumulation or lipid storage. See, for example, Tontonoz, P., Hu, E., and Spiegelman, B. M., Curr. Opin. Genet. Dev., (1995), Vol. 5, pp 571-576. Examples of these diseases are obesity, osteoporosis, and acne. Briefly, in one aspect, the present invention discloses compounds of formula IA or IB,
  • R is H or -OCH 3 ;
  • R 2 is a hydrophobic organic group with molecular weight less than 500
  • R 3 is H, C ⁇ alkyl, or phenyl optionally substituted with 1 or 2 groups selected from C- .3 alkyl, C ⁇ alkoxy, and halogen.
  • the compounds of this invention are capable of binding to the ligand-binding domain of a nuclear receptor and arylating a cysteine residue of the receptor.
  • X is Cl, F, or Br. Most preferably, X is Cl.
  • R 2 is
  • R 4 and R 5 are independently hydrogen or halogen. Most preferably, R 4 and R 5 are both H, both chloro, or one is H and one is iodo.
  • R 3 is hydrogen, mono-substituted or un-substituted phenyl, or C ⁇ alkyl. Most preferably, R 3 is H.
  • the present invention discloses a method of inhibiting the activity of a nuclear receptor by arylating a cysteine residue within the ligand-binding domain of said receptor.
  • the present invention discloses a method for associating a particular disease or condition with a particular nuclear receptor, for example PPARgamma. By “associating” is meant that the particular disease or condition can be treated by the administration of a compound that activates or deactivates the particular nuclear receptor.
  • the present invention provides a method for the treatment of a nuclear receptor mediated disease or condition by administration of a compound that activates or deactivates the particular nuclear receptor that was associated with said disease or condition using the method of this invention.
  • Preferred compounds of this invention are capable of binding to the ligand-binding domain of a nuclear receptor and arylating a cysteine residue of the receptor.
  • compounds of formula IA or IB can be prepared, tested for binding to a particular receptor and analysed for arylation of the receptor.
  • a library of compounds of formula IA or IB can be prepared. The library can then be screened using a binding assay to identify members of the library that show affinity to a particular nuclear receptor, for example PPAR-gamma.
  • Arylating compounds that bind to a nuclear receptor and therefore block its functional activity in a cell line, cell culture, tissue, or whole animal can be used to associate the nuclear receptor with a mammalian disease.
  • arylating compounds that block PPAR-gamma activity inhibit adipogenesis, thereby suggesting that PPARgamma plays a role in adipogenesis.
  • some nuclear receptors are associated with particular diseases or conditions, there may be more diseases or conditions that can be treated or prevented by a compound that activates or deactivates that receptor. Some nuclear receptors have no known utility.
  • new disease-receptor associations can be discovered. Once these new associations are discovered, then new drugs for these diseases can be discovered by searching for compounds that activate or deactivate the receptor.
  • the present invention provides new methods for drug discovery, and consequently new drugs for prevention and treatment of human diseases and conditions.
  • Suitable compounds of the present invention include: N-phenyl-2-chloro-5-nitro-benzamide, N-(2,4-dichlorophenyl)-2-chloro-5-nitro-benzamide, N-(4-iodophenyl)-2-chloro-5-nitro-benzamide,
  • a particularly preferred compound of the present invention is N-phenyl- 2-chloro-5-nitro-benzamide.
  • alkyl straight-chain and branched-chain alkyl chains unless otherwise indicated.
  • the compounds of this invention can be prepared by standard organic chemistry as illustrated by the accompanying working examples. The following examples are set forth to illustrate the synthesis of some particular compounds of the present invention and to exemplify general processes. Accordingly, the following Examples section is in no way intended to limit the scope of the invention contemplated herein.
  • Example 1 N-phenyl-2-chloro-5-nitro-benzamide To a stirred solution of 2-chloro-5-nitro-benzoyl chloride (5.03 g, 22.9 mmol) and triethylamine (3.51 mL, 25.1 mmol) in CH 2 CI 2 maintained under nitrogen at 0°C was added dropwise aniline (2.19 mL, 24.0 mmol). The resulting solution was stirred for 5 minutes at 0°C and then for 15 minutes at room temperature. This solution was then diluted with EtOAc (300 mL) and washed sequentially with 1.0 M HCI, water, 1.0 M NaHCO 3 and brine (100 mL each).
  • Example 2 N-(2,4-dichlorophenyl)-2-chloro-5-nitro-benzamide
  • Example 3 N-(4-iodophenyl)-2-chloro-5-nitro-benzamide
  • Test compounds were assayed for binding to the human PPAR- gamma receptor ligand binding domain by scintillation proximity assay (SPA) as described in Nichols, J. S., Parks, D. J., Consler, T. G., and Blanchard, S. G., Anal. Biochem., Vol. 257, pp.112-119, and Vol. 263, p 126 (1998),.
  • SPA scintillation proximity assay
  • Binding to the PPAR- ⁇ and PPAR- ⁇ ligand binding domains was determined in a similar manner using the previously described radioligands [ 3 H]-GW2331 (Kliewer, S.A. et. al., and Lehmann, J.M. Proc. Natl. Acad Sci USA (1997) Vol.94 pp. 4318-4323) and [ 3 H]-GW2433 (Brown, P.J., Smith-
  • the buffer used for the PPAR- ⁇ and PPAR- ⁇ SPA was 50 mM KCI, 2 mM EDTA, 5 mM CHAPS, 0.1 mg/mL BSA, 10 mM DTT, and 50 mM Tris (2- amino-2-hydroxymethyl-1 ,3-propanediol) pH 8 (Buffer A).
  • the Tris was replaced with HEPES (N-[2-Hydroxyethyl]piperazine-N'-[2- ethanesufonic acid]) and the pH was 7 (Buffer B). Analysis of the apparent binding affinity of the compound of Example
  • CV-1 cells were maintained in DME High Glucose medium (Irvine Scientific) supplemented with 10% fetal bovine serum and 2 mM Glutamine. Cells were split into D-MEM/F-12 medium (Gibco) supplemented with 10 % charcoal stripped fetal bovine serum for 3 d before harvesting. Cells were harvested into D-MEM/F-12 medium (Gibco) supplemented with 10 % charcoal stripped fetal bovine serum and counted. Cells were seeded at a density of 24,000 cells per well into 96-well plates and incubated overnight at 5% CO 2 and 37 °C. Cells were transfected for 6 to 20 hours based on the
  • Lipofectamine protocol with the following amounts of DNA per well: 2 ng PSG5 GAL4-human PPAR-gamma, 8 ng UAS-tk-SPAP, 25 ng beta-gal, 45 ng pBluescript. See Lehmann, J. M. et al., J. Biol. Chem., (1995), Vol. 270, pp 12953-12956 and Brown, P. J. et al., Chem. Biol., (1997), Vol. 4, pp 909-918. Cells were incubated overnight at 5 % CO2 and 37 °C. Test compounds were solublized to 10 mM in DMSO.
  • Test compounds were then serially diluted from 1e-5 M to 1e-10 M into D-MEM/ F-12 (Gibco) medium supplemented with 10% delipidated and charcoal stripped calf serum (Sigma) heat inactivated at 60 °C for 30 minutes, 2 mM Glutamine, and Pen-Strep.
  • This medium into which the test compounds were diluted also contained 100 nM rosiglitazone.
  • These test compound dilutions were added 100 microliters/well to the transfected cell plates after the transfection media were aspirated.
  • DMSO controls and 1 micromolar rosiglitazone controls were added to each cell plate. Cells were incubated overnight at 5 % CO 2 and 37 °C.
  • Blocking PPAR gamma Binding PPARy (in Buffer A) immobilised on SPA beads was incubated with 1 ⁇ M of the compound of Example 1 ( ⁇ in the graph below) or rosiglitazone (• in the graph below) for 1 hour. (Buffer A was used throughout this experiment.) This pretreating ligand was removed by two sequential steps of centrifugation followed by resuspension of the beads in fresh buffer. Recovery of binding was assessed by addition of [ 3 H]-rosiglitazone to an aliquot of the washed bead suspension followed by scintillation proximity assay to monitor the recovery of radioligand binding as a function of time.
  • Biotinylated receptor immobilized on streptavidin-coated SPA beads was exposed either to vehicle, 1 ⁇ M the compound of Example 1 , or to rosiglitazone. Following incubation for one hour, the pretreating ligand was removed from immobilized receptor and radioligand was added. Recovery of binding as a function of time was assessed by SPA. When PPARy was treated with the compound of Example 1 in this manner, persistent inhibition of [ 3 H]-rosiglitazone binding to the receptor was observed. Little recovery of binding activity was observed at times up to 24 hours after removal of pretreating compound, suggesting that the inhibition was irreversible.
  • the standard conditions for the PPAR SPAs included 10 mM of the reducing agent dithiothreitol (DTT) in the assay buffers.
  • DTT dithiothreitol
  • the second reason for use of DTT in the assay buffer was to act as a scavenger for nonspecific protein modifying reagents. As the concentration of DTT was more than six orders of magnitude above the concentration of receptor protein in the assay ( ⁇ 5 nM) the possibility of nonspecific receptor modification seemed unlikely.
  • the X-ray crystal structure of the PPARy ligand binding domain shows that the single cysteine residue in the LBD is located in helix 3, which defines part of the ligand binding site. See, R. T. Nolte et al, Nature, Vol. 395, pp 137-143 (1998).
  • the following UV-Visible absorption study and LC- Mass Spec. Studies are designed to study the effect of compounds on this cysteine. UV-Visible Absorption
  • Example 1 had > 50 % inhibition of lipogenesis induced by 150 nM rosiglitazone in this adipocyte differentiation assay.
  • Example 6 N-(1 -tricyclo[3.3.1.13,7]dec-1 -ylethyl)-2-chloro-5-nitro-benzamide
  • the title compound was prepared and is useful for binding to and arylating CAR.
  • CAR For information on CAR, see, for example, Forman, B. M. et al., Nature (1998), 395, 612-615.
  • Example 7 N-(2-ethoxyphenyl)-N-(6-bromo-1 H-benz[de]isoquinoline- 1 ,3(2H)-dioxo-eth-2-yl-)-2-chloro-5-nitro-benzamide
  • LXR For information on LXR, see, for example, Peet, D. J. et al., Curr. Opin. Genet. Dev. (1998), 8, 571-575.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Obesity (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne de nouveaux ligands de récepteurs nucléaires de formule (IA) ou (IB). Ces composés servent à aryliser une cystéine dans un récepteur nucléaire.
EP00916297A 1999-03-16 2000-03-13 Composes d'arylation de recepteurs nucleaires Withdrawn EP1161412A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US12463599P 1999-03-16 1999-03-16
US124635P 1999-03-16
PCT/US2000/006537 WO2000055118A1 (fr) 1999-03-16 2000-03-13 Composes d'arylation de recepteurs nucleaires

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EP1161412A1 true EP1161412A1 (fr) 2001-12-12

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EP00916297A Withdrawn EP1161412A1 (fr) 1999-03-16 2000-03-13 Composes d'arylation de recepteurs nucleaires

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EP (1) EP1161412A1 (fr)
JP (1) JP2002539185A (fr)
AU (1) AU3742100A (fr)
WO (1) WO2000055118A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2407587A1 (fr) * 2000-04-28 2001-11-08 Sankyo Company, Limited Modulateurs de ppar.gamma.
WO2003035602A1 (fr) * 2001-10-25 2003-05-01 Sankyo Company, Limited Modulateurs lipidiques
MXPA04006203A (es) 2001-12-21 2004-10-15 Pharmacia Corp Moduladores aromaticos del receptor x de higado de tioeter.
EP1511723A1 (fr) 2002-05-24 2005-03-09 Pharmacia Corporation Modulateurs de recepteur x hepatique a base de sulfone
CA2486644A1 (fr) 2002-05-24 2003-12-04 Pharmacia Corporation Modulateurs des recepteurs x du foie a structure anilino
DE602004031339D1 (de) * 2003-06-13 2011-03-24 S A L V A T Lab Sa Neue benzamide als ppaty-modulatoren
GB0419850D0 (en) * 2004-09-07 2004-10-13 Angeletti P Ist Richerche Bio Therapeutic agents
KR101815193B1 (ko) * 2015-12-29 2018-01-30 (주)스파크바이오파마 PPARγ 인산화 저해제 및 이를 포함하는 약학적 조성물

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US5449691A (en) * 1991-12-31 1995-09-12 Sterling Winthrop Inc. 3,4-disubstituted anilines-immunomodulating agents
US5756448A (en) * 1992-02-26 1998-05-26 The General Hospital Corporation Constitute activator of retinoid (CAR) receptor polypeptides
AU700706B2 (en) * 1992-11-25 1999-01-14 Ligand Pharmaceuticals, Inc. RXR homodimer formation and bridged bicyclic aromatic compounds and their use in modulating gene expression
WO1994015901A1 (fr) * 1993-01-11 1994-07-21 Ligand Pharmaceuticals Inc. Composes activant selectivement les recepteurs de retinoides x
FR2733684B1 (fr) * 1995-05-03 1997-05-30 Cird Galderma Utilisation de retinoides dans une composition cosmetique ou pour la fabrication d'une composition pharmaceutique
JPH0959236A (ja) * 1995-08-23 1997-03-04 Dai Ichi Seiyaku Co Ltd ベンズアミド化合物
US5663357A (en) * 1995-11-22 1997-09-02 Allergan Substituted heteroarylamides having retinoid-like biological activity
AU5928898A (en) * 1997-01-24 1998-08-18 Regents Of The University Of California, The Use of fxr, pparalpha and lxralpha activators to restore barrier function, promote epidermal differentiation and inhibit proliferation
SE9704544D0 (sv) * 1997-12-05 1997-12-05 Astra Pharma Prod Novel compounds
RU2226529C2 (ru) * 1997-12-19 2004-04-10 Шеринг Акциенгезельшафт Производные ортоантраниламида в качестве антикоагулянтов, фармацевтическая композиция и способ лечения

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WO2000055118A1 (fr) 2000-09-21
JP2002539185A (ja) 2002-11-19
AU3742100A (en) 2000-10-04

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