WO2003089441A1 - Mercaptans tricycliques, leur procede de production et leur utilisation - Google Patents

Mercaptans tricycliques, leur procede de production et leur utilisation Download PDF

Info

Publication number
WO2003089441A1
WO2003089441A1 PCT/EP2003/004084 EP0304084W WO03089441A1 WO 2003089441 A1 WO2003089441 A1 WO 2003089441A1 EP 0304084 W EP0304084 W EP 0304084W WO 03089441 A1 WO03089441 A1 WO 03089441A1
Authority
WO
WIPO (PCT)
Prior art keywords
mercaptomethyl
thiazolo
alkyl
phenyl
thieno
Prior art date
Application number
PCT/EP2003/004084
Other languages
German (de)
English (en)
Inventor
Uwe Klausmeier
Jochen Heinicke
Original Assignee
Ibfb Gmbh
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 Ibfb Gmbh filed Critical Ibfb Gmbh
Priority to AU2003232486A priority Critical patent/AU2003232486A1/en
Publication of WO2003089441A1 publication Critical patent/WO2003089441A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems
    • 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]

Definitions

  • the present invention relates to tricyclic mercaptans of the general formula I.
  • n the numbers 0, 1 or 2
  • R1 represents a hydrogen atom or a methyl group
  • A is a fused-on 5- to 7-membered cycloalkyl ring or a 5- to 7-membered cycloheteroalkyl ring bonded via two carbon atoms with an oxygen, nitrogen or sulfur atom, or a heteroaromatic bond bonded via two carbon atoms, the heteroaromatic being mono by a radical R2 as defined below -, can be di- or tri-substituted and the substituents can be the same or different,
  • R2 is hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, cyano, trifluoromethyl, C6-C12 aryl, heteroaryl, C7-C13 aralkyl and a heterocycle bonded via a C1-C3 alkyl group, where the above-mentioned aromatics and heterocycles can optionally be substituted by a radical R3,
  • R3 denotes C1-C4 alkyl, C1-C4 alkoxy, halogen, -COR4, -S02R4, -OCOR4, - COOR5, -S03R5, -CONR5R6, -S02NR5R6 or-NR5R6, in which:
  • R4 C1-C6 alkyl, C6-C12 aryl, benzyl
  • R5 and R6 are independently hydrogen, C1-C6 alkyl, C6-C12 aryl, 07-C9 aralkyl or R4 and R5 together form a 5- or 6-membered ring which contains a nitrogen atom and / or an oxygen or a sulfur - or contain a second nitrogen atom and can optionally be substituted by a C1-C4-alkyl group, a phenyl or a benzyl radical,
  • R2 if A is thieno, also -CO-R7, -S02-R7, -COOR8, CO-NR7R8, - (CH2) m -phenyl, - (CH2) m -COOR8, and a fused-on C4-C7-cycloalkyl ring, which contain an oxygen, sulfur or nitrogen atom and can optionally be substituted by a C1-C4-alkyl group, a phenyl or benzyl radical, where
  • R7 alkyl C1-C6, phenyl, benzyl and
  • R8 hydrogen, alkyl C1-C6, phenyl, benzyl,
  • TIMPs matrix metalloproteinases
  • MMPs cut a path through dense collagenous connective tissue and in particular also through the basement membrane of the vessels and thereby enable the cancer cells to migrate out of the tumor group, immigrate into the vascular system and form daughter tumors elsewhere.
  • MMPs play another crucial role in the supply of blood to the growing tumor by cutting the way for the newly formed blood vessels through the collagenous connective tissue and are therefore responsible for this vascularization of the growing tumor (Shapiro, SD .: Matrix metalloproteinase degradation of extracellular matrix: biological consequences.Current Opinion in Cell Biology 10 (1998) 602-608).
  • UV-induced erythema Another relevant medical result of inadequately inhibited effects of MMPs is UV-induced erythema, which among other things occurs as a result of intense sun exposure.
  • the high-energy UV rays of sunlight and tanning devices activates the inactive procollagenases in the irradiated skin, which subsequently split collagen in the connective tissue and the blood capillaries and are therefore responsible for the symptoms of sunburn.
  • These active substances of the first generation generally have a proteinogenic structure and are structurally related to natural inhibitors, which are special proteins.
  • These proteinogenic or pseudoproteinogenic substrate analogues have as a structure relement a zinc binding group that chelates the zinc ion in the active center of the MMPs.
  • the aim of the invention is to meet the urgent need for drugs with a non-proteinogenic structure which do not have the disadvantages of the active ingredients which have hitherto been on the market.
  • new active substances with an MMP-inhibiting effect which are sufficiently stable and readily absorbable, have better pharmacokinetic properties and, above all, do not have any undesirable side effects and cytotoxic reactions.
  • the object of the invention is therefore to find new chemical substances of non-proteinogenic structure which have an MMP-inhibiting effect. It is another object of the invention to process for making such compounds as well to provide appropriate medicinal products containing these compounds.
  • the object is achieved by producing and finding the MMP-inhibiting action of the new tricyclic mercaptans of the general formula I,
  • n the numbers 0, 1 or 2
  • R1 represents a hydrogen atom or a methyl group
  • A is a fused-on 5- to 7-membered cycloalkyl ring or a 5- to 7-membered cycloheteroalkyl ring bonded via two carbon atoms with an oxygen, nitrogen or sulfur atom, or a heteroaromatic bond bonded via two carbon atoms, the heteroaromatic being mono by a radical R2 as defined below -, can be di- or tri-substituted and the substituents can be the same or different,
  • R2 denotes hydrogen, halogen, 01-06 alkyl, 01-04 alkoxy, 01-04 alkylthio, cyano, trifluoromethyl, 06-012 aryl, heteroaryl, 07-013 aralkyl and a heterocycle bonded via an 01-03 alkyl group, where the above-mentioned aromatics and heterocycles can optionally be substituted by a radical R3,
  • R3 means 01-04 alkyl, 01-04 alkoxy, halogen, -C0R4, -S02R4, -0C0R4, - C00R5, S03R5, -CONR5R6, -S02NR5R6 or -NR5R6, in which:
  • R4 01-06 alkyl, 06-012 aryl, benzyl
  • R5 and R6 are independently hydrogen, C1-C6 alkyl, 06-012 aryl, 07-09 aralkyl or R4 and R5 together form a 5- or 6-membered ring which contains a nitrogen atom and / or an oxygen or a sulfur - or contain a second nitrogen atom and may optionally be substituted with a C1-C4 alkyl group, a phenyl or a benzyl radical; also means
  • R2 if A is thieno, also -CO-R7, -S02-R7, -COOR8, CO-NR7R8, - (CH2) m -phenyl, - (CH2) m -COOR8, and a fused-on C4-C7-cycloalkyl ring, which contain an oxygen, sulfur or nitrogen atom and can optionally be substituted by a C1-C4-alkyl group, a phenyl or benzyl radical, where
  • R7 alkyl 01-06, phenyl, benzyl and
  • R8 hydrogen, alkyl 01-06, phenyl, benzyl,
  • alkyl, alkoxy, alkylthio and alkoxycarbonyl groups mentioned as radicals R2 to R10 can be shown or undisplayed or open-chain or cyclic. They can also contain substituents, such as halogen atoms, cyano, carboxy, nitrile, carbamoyl, 01 -C4 alkoxy, phenyl, 01-04 alkoxycarbonyl, 01-04 alkylcarboxy, 01-04 N-alkylcarbamoyl, 01-04 N-Dialkylcarbamoyl-, Hydroxy-, Nitro.-, S0 3 H-, Sulfamoyl-, 01 -04 N-Alkylsulfamoyl, 01 -04 Dialkylsulfamoyl and Trifluoromethyl- Have groups or further open-chain or cyclic groups with heteroatoms (for example with N, S and / or O), in which the heteroatoms can optionally be part of a heterocycle.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • a thiophene ring is preferred as radical "A". Furthermore, pyrrole, thiazole, furan, imidazole, pyrazole, pyridine, pyrimidine and pyrazine rings / ring systems are preferred.
  • Under 01 -C4 alkyl are methyl, ethyl., N-propyl, isopropyl, n-butyl, isobutyl., Sec. Butyl. and to understand tert-butyl.
  • 01 -C6 alkyl includes Methyl, ethyl., N-propyl, isopropyl, n-butyl, isobutyl., Sec. Butyl., Tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl etc. and their cyclic equivalents.
  • 01 -C4 alkoxy means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy groups.
  • C6-C12 aryl e.g. To understand phenyl, tolyl, xylyl, naphthyl, biphenyl ring systems.
  • n 0 or 1
  • R1 a hydrogen atom or a methyl group
  • A is a fused-on 5- to 7-membered cycloalkyl ring or a 5- to 7-membered cycloheteroalkyl ring bonded via two carbon atoms with one oxygen, nitrogen or sulfur atom, or a six-membered heteroaromatic bond with one, two or three nitrogen atoms as hetero atoms or five-membered with a nitrogen atom or five-membered with an oxygen or sulfur atom or five-membered with a nitrogen atom and one oxygen or one sulfur atom or five-membered with two nitrogen atoms as heteroatoms or five-membered with two nitrogen atoms and one sulfur atom or five-membered with three nitrogen atoms as heteroatoms, where the heteroaromatic in the carbon skeleton can be mono- or disubstituted by a radical R2 as defined below and the substituents can be the same or different.
  • R2 means hydrogen, halogen, alkyl C1-C4, alkoxy C1-C4, cyano-, trifluoromethyl, phenyl, heteroaryl (monocyclic with a heteroatom 0, N or S), benzyl, phenylethyl, heteroarylakyl (monocyclic, the heteroaromatic with a heteroatom O, N or S, alkyl 01-03), where the above-mentioned aromatics and heteroaromatics can optionally be substituted by a radical R3,
  • R3 denotes alkyl 01 -C4, alkoxy 01 -C4, halogen, -C0R4, -S02R4, -S03R5, - OCOR4, -COOR5, -CONR5R6, -S02NR5R6 or-NR5R6, in which:
  • R4 alkyl 01 -C6, phenyl, benzyl,
  • R5 and R6 are independently hydrogen, alkyl 01-04, phenyl, aralkyl 07-09 or R4 and R5 together form a 5- or 6-membered ring which contains a nitrogen atom and / or an oxygen or a sulfur or contain a second nitrogen atom and may optionally be substituted by a 01 -C4 alkyl group, a phenyl or a benzyl radical; also means R2 if A is thieno, also -CO-R7, -S02-R7, -COOR8, CO-NR7R8, - (CH2) m -phenyl, - (CH2) m -COOR8.
  • R7 alkyl 01 -C4, phenyl, benzyl and
  • R8 hydrogen, alkyl 01 -C4, phenyl, benzyl can be
  • n 0 or 1
  • R1 a hydrogen atom or a methyl group
  • A is a fused-on 5- to 7-membered cycloalkyl ring or a 5- to 7-membered cycloheteroalkyl ring bonded via two carbon atoms with an oxygen, nitrogen or sulfur atom, or a six-membered heteroaromatic bond with two or three nitrogen atoms as heteroatoms or with five members a nitrogen atom or five-membered with an oxygen or sulfur atom or five-membered with two nitrogen atoms or five-membered with a nitrogen atom and one oxygen or one sulfur atom or five-membered with three nitrogen atoms or five-membered with two nitrogen atoms and one sulfur atom, the heteroaromatic in the carbon skeleton being represented by one as below defined radical R2 can be mono- or disubstituted and the substituents can be the same or different, R2 means hydrogen, halogen, C1 -C4 alkyl, 01 -C4 alkoxy, cyano-, trifluoromethyl,
  • R3 means C1-C4 alkyl, C1-C4 alkoxy, halogen, -COR4, -S02R4, -S03R5, - C00R5, -CONR5R6, -S02NR5R6 or -NR5R6, in which mean:
  • R4 01 -C4 alkyl, phenyl, benzyl,
  • R5 and R6 are independently hydrogen, 01 -C4 alkyl, phenyl or the R4 and R5 together form a 5- or 6-membered ring which contain another nitrogen, oxygen or sulfur atom and optionally with a C1-C4 alkyl group can be substituted; also means
  • R2 if A is thieno also -CO-R7, -S02-R7, -C00R8, CO-NR7R8, - (CH2) m -phenyl, - (CH2) m -C00R8. as well as a fused-on C4-C7 cycloalkyl ring which contain an oxygen, sulfur or nitrogen atom and can optionally be substituted by a 01 -C4-alkyl group, a phenyl or benzyl radical, where
  • R7 01 -C4 alkyl phenyl, benzyl and
  • R8 hydrogen, 01 -C4 alkyl, phenyl, benzyl can be
  • R1 H, CH3
  • A fused five- to seven-membered cycloalkyl ring or a fused five- to seven-membered cycloheteroalkyl ring with an oxygen or sulfur atom or a heteroaromatic bonded via two carbon atoms, this six-membered with one, two or three nitrogen atoms as heteroatoms or five-membered with a nitrogen atom, which may be substituted by a C1 to C3 alkyl group or five-membered with an oxygen or sulfur atom or five-membered with a nitrogen atom, which can be substituted by a C1 to 03 alkyl group and an oxygen or a sulfur atom or five-membered with two nitrogen atoms as heteroatoms, the carbon atoms in the heteroaromatic being substituted by a like radical R2 defined below can be mono-, di- or tri-substituted and the substituents can be identical or different
  • R2 fluorine, chlorine, bromine, iodine, 01 to C6 alkyl (straight-chain or branched),
  • R3 H, C1 to 04 alkyl (straight or branched), 03 to 06 cycloalkyl, phenyl
  • the present invention relates to the compounds of the general formula I in the form of their racemates, their enantiomers and, if appropriate, in the form of their diastereomers and the possible mixtures of these.
  • the compounds of the general formula I obtained can optionally be converted into their enantiomers and / or diastereomers by methods known per se (cf., for example, Allinger, NL and Elliel EL in "Topics in Stereochemistry” Vol. 6, Wiley Interscience, 1971) be separated.
  • the enantiomers are separated preferably by chromatography on chiral phases or by recrystallization from an optically active solvent or by reaction with a chiral substance which forms diastereomeric derivatives with the racemic compound (for example salts, esters, disulfides), in particular carboxylic acids and their activated derivatives, separation of the mixture of diastereomers obtained in this way (for example by chromatography and / or crystallization) and subsequent release of the pure enantiomers using a suitable reagent.
  • a chiral substance which forms diastereomeric derivatives with the racemic compound for example salts, esters, disulfides
  • carboxylic acids and their activated derivatives for example carboxylic acids and their activated derivatives
  • the present mixture of diastereomers can first be separated into the pure diastereomers by methods known per se (for example column chromatography and / or crystallization) and then, as mentioned above, these diastereomers can be separated into the corresponding enantiomers.
  • methods of asymmetric synthesis known per se to the person skilled in the art or enantiomerically pure synthesis building blocks can be used.
  • the tricycles of the general formula I according to the invention contain an asymmetric carbon atom in the thiazolo or thiazino ring. In addition, additional centers of asymmetry may be present with appropriate substitution.
  • the present invention also relates to prodrugs of the compounds of the general formula I in which the mercapto function is substituted by a radical which can be split off in vivo.
  • residues which can be split off in vivo are acyl groups, acyloxycarbonyl groups, alkoxycarbonyl groups, carbamoyl groups, phosphate residues.
  • the compounds according to the invention are used as MMP inhibitors, in particular for the treatment of diseases of the rheumatic type, for the treatment of non-specific inflammatory reactions (for example a UV-induced erythema) and allergies and to prevent the growth or metastasis of tumors.
  • the mercaptans of the above general formula I according to the invention can be obtained by reacting the analog iodides, bromides, chlorides or tosylates of the general formula II,
  • Tricyclic precursors of the general formula II can be obtained by cyclization of the corresponding N3-alkenyl-substituted pyrimidine-2 (1 H) -thione-4 (3H) -ones of the general formula III
  • aminocarboxylic acid derivative of the general formula IV For example, an aminocarboxylic acid derivative of the general formula IV
  • the open-chain thioureas initially formed in this process cyclize thermally and / or base-catalyzed to the corresponding N3-alkenyl-substituted pyrimidine-2 (1H) -thione-4 (3H) -ones of the general formula III.
  • R11 alkyl or alkenyl from C1 to C4 can be with an amine of the general
  • the open-chain thioureas which in turn initially arise, cyclize, as described above, to the corresponding N3-alkenyl-substituted pyrimidine-2 (1H) -thione-4 (3H) -ones of the general formula III.
  • Examples of special approaches to synthetic building blocks of types IV and VI are: RW Sabnis, nen, The Gewald-Synthesis, Sulfur Reports 16 (1994) p. 1 ff. (Thiophene); RW Sabnis, DW Ragnekar, ND Sonawane, 2-Aminothiophenes by the Gewald Reaction, J. Heterocyclic Chem. 36 (1999) 333 ff.
  • reactive groups which may be present can be protected by customary protective groups (see, for example, Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 2nd ed. 1991, Wiley & Sons, New York).
  • customary protective groups see, for example, Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 2nd ed. 1991, Wiley & Sons, New York.
  • the necessity and type of the required protective group from the substitution pattern and type of reaction are recognizable for the person skilled in the art.
  • Transl.) EN; 9; 1973; 1169-1170 are added 1: 1 in 30 ml THF / ethanol and with 12 mmol thiourea under DO or HPLC control at a bath temperature of approx. 100 ° C until complete conversion heated. If crystallization does not start when cooling, ethyl acetate is added until the mixture becomes cloudy and the then separating isothiuronium salt is separated off. This is saponified in 1N NaOH with the addition of a little ethanol and under a nitrogen atmosphere at a bath temperature of 50 ° C. The course of the reaction is monitored by DC or HPLC chromatography.
  • the mixture is acidified with 1 N HOl while cooling with ice, the precipitate which forms is filtered off with suction, washed with water, dried and, if necessary, recrystallized from ethanol or ethyl acetate / heptane.
  • MMP-2 Matrix Metalloproteinase-2
  • MMP-2 (gelatinase) is released from cultured dermal fibroblasts in considerable quantities into the culture medium and is therefore easily accessible.
  • the secreted and inactive proform of the enzyme can be converted into the enzymatically active form by trypsin activation or by treatment with organic mercury compounds.
  • human dermal fibroblasts are obtained and cultivated according to established standard methods and the cell-free culture supernatant is treated with trypsin. Trypsin is then inactivated with a specific inhibitor (TLCK) and the active MMP-2 is partially purified by affinity chromatography on gelatin-Sepharose and subsequent gel filtration on Sepharose. MMP-2 was identified and characterized by the availability of a commercial immunoassay.
  • TLCK specific inhibitor
  • the solution is 15 min. centrifuged at 16,000 rpm on an SS-34 rotor at 4 ° C and filtered over glass wool.
  • the filtrate is batched with gelatin agarose, which has been equilibrated with binding buffer, and shaken on ice for 1 hour.
  • the loaded gelatin agarose is transferred to a column and rinsed protein-free with at least 10 vol. Binding buffer.
  • the bound MMP-9 is eluted with 2 gel volumes of binding buffer plus 5% (v / v) DMSO.
  • the eluate can be separated by gel filtration on Sephadex G-75 for buffer exchange and simultaneous removal of small impurities on MMP-2.
  • Buffer I (20 mM Tris-HCl pH 7.5, 5 mM CaCl 2 , 100 mM NaCl, 0.1% (v / v) Triton X-100) is used for this.
  • the eluate obtained in this way contains MMP-9 in the three known states: monomer, homodimer, heterodimer.
  • the purity of the enzyme is about 90%, with the remaining foreign proteins being fibronectin and extremely small amounts of TIMP's.
  • the latent enzyme is 30-60 min. Incubation at 37 ° C with 1/100 vol. Trypsin (10 mg / ml) activated. Trypsin is inhibited by adding 1 mM PMSF or with a specific inhibitor (TLCK).
  • the use of the catalytic domain of the MMP-8 as a further test enzyme is chosen because it has a high stability and is also present as an active enzyme and therefore does not need to be activated, which as a of the most common causes of error comes into question because the mercury compounds used for activation often interfere with the test system or the enzyme and can thereby falsify the measurement results.
  • We align the cloning strategy so that instead of the entire enzyme, only its enzymatically active catalytic domain is cloned in E. coli.
  • the cloning and expression of the recombinant catalytic domain of the MMP-8 was carried out in accordance with the information provided by SCHNIERER et al. (Schnierer S, Kleine T, Gote T, Hillemann A Knäuper V, Tschesche H: The recombinant catalytic domain of human neutrophil collagenase lacks type I collagen Substrate specificity. Biochem Biophys Res Comm (1993) vol. 191 No. 2, 319-326 ) carried out.
  • the fluorescent group Mca is separated from the internal quencher Dpa by enzymatic cleavage of the synthetic substrate Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH 2 by the respective collagenase.
  • There is a strong increase in fluorescence in the measurement batch which can be quantified on the fluorimeter ( ⁇ ex 328 nm, ⁇ em 393 nm) and is linear within the first few minutes.
  • a certain specificity of the test for matrix metalloproteinases results on the one hand from the amino acid sequence -Pro-Leu-Gly-Leu- in the substrate and on the other hand from the chosen incubation conditions.
  • Matrix metalloproteinases cleave the substrate at the Gly-Leu bond.
  • the proteolytic residual activity of preincubated batches of enzyme and inhibitor is measured, the substrate and enzyme concentration being kept constant and the inhibitor concentration varied. Three series of measurements with different substrate concentrations were recorded for each inhibitor tested.
  • the enzyme activity is calculated in fluorescence units per minute from the time-dependent increase in fluorescence.
  • the Kr values were determined graphically by the method of DIXON (1953) by plotting the reciprocal reaction rate 1 / v (y-axis) against inhibitor concentration (x-axis).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention se rapporte à des mercaptans tricycliques, à leurs tautomères, stéréoisomères, sels physiologiquement acceptables comportant des bases et des acides inorganiques et organiques ainsi qu'à des substances similaires, qui peuvent servir d'inhibiteurs de métalloprotéinases (MMP). Ces substances peuvent être utilisées en tant que médicaments pour traiter des rhumatismes et des réactions inflammatoires non spécifiques, entre autres en cas de coup de soleil ou d'allergie, et dans le cadre d'un traitement anticancéreux. Lesdites substances tricycliques de formule générale (I) comportent un atome de carbone asymétrique dans le cycle triazolo ou triazine. En cas de substitution correspondante, d'autres centres d'asymétrie sont en outre possibles.
PCT/EP2003/004084 2002-04-22 2003-04-17 Mercaptans tricycliques, leur procede de production et leur utilisation WO2003089441A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003232486A AU2003232486A1 (en) 2002-04-22 2003-04-17 Tricyclic mercaptans, method for their production and the use thereof as mmp inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10217814.3 2002-04-22
DE10217814A DE10217814A1 (de) 2002-04-22 2002-04-22 Neue tricyclische Mercaptane, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel

Publications (1)

Publication Number Publication Date
WO2003089441A1 true WO2003089441A1 (fr) 2003-10-30

Family

ID=29224635

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/004084 WO2003089441A1 (fr) 2002-04-22 2003-04-17 Mercaptans tricycliques, leur procede de production et leur utilisation

Country Status (3)

Country Link
AU (1) AU2003232486A1 (fr)
DE (1) DE10217814A1 (fr)
WO (1) WO2003089441A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11318134B2 (en) 2018-01-10 2022-05-03 Recurium Ip Holdings, Llc Benzamide compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10046728C1 (de) * 2000-09-21 2001-09-27 Ibfb Gmbh Privates Inst Fuer B Tricyclische mercaptomethylsubstituierte 2,3-Dihydro-chinazolin-5-one und 2,3-Dihydro-benzo[1,2,4,]-thiadiazin-5,5-dioxide als Matrix Metalloproteinase (MMP) Inhibitoren

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10046728C1 (de) * 2000-09-21 2001-09-27 Ibfb Gmbh Privates Inst Fuer B Tricyclische mercaptomethylsubstituierte 2,3-Dihydro-chinazolin-5-one und 2,3-Dihydro-benzo[1,2,4,]-thiadiazin-5,5-dioxide als Matrix Metalloproteinase (MMP) Inhibitoren

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11318134B2 (en) 2018-01-10 2022-05-03 Recurium Ip Holdings, Llc Benzamide compounds
US11344546B2 (en) 2018-01-10 2022-05-31 Recurium IP Holding, LLC Benzamide compounds
US11590126B2 (en) 2018-01-10 2023-02-28 Recurium Ip Holdings, Llc Benzamide compounds
US11813259B2 (en) 2018-01-10 2023-11-14 Recurium Ip Holdings, Llc Benzamide compounds
US11813260B1 (en) 2018-01-10 2023-11-14 Recurium Ip Holdings, Llc Benzamide compounds

Also Published As

Publication number Publication date
AU2003232486A1 (en) 2003-11-03
DE10217814A1 (de) 2003-11-13

Similar Documents

Publication Publication Date Title
EP1427730B1 (fr) Nouvelles dihydropteridinones, procedes pour les produire et leur utilisation en tant que medicaments
DE60030002T2 (de) Für den adenosin-a1-a2a-und-a3-rezeptor spezifische verbindungen und verwendungen davon
DE69733348T2 (de) Farnesyltransferase inhibitoren
US7749996B2 (en) Heterotricyclic metalloprotease inhibitors
US20080221095A1 (en) Metalloprotease inhibitors containing a heterocyclic moiety
EP0254245A1 (fr) Hétrazépines et leurs procédés de préparation
WO2008063670A1 (fr) Inhibiteurs de métalloprotéases hétérobicycliques
DE3502392A1 (de) Neue thieno-triazolo-1,4-diazepino-2- carbonsaeureamide, verfahren zu ihrer herstellung und pharmazeutische zusammensetzungen
DE3724164A1 (de) Neue 1,4-benzodiazepine, ihre herstellung und verwendung
DE602005008633D1 (de) Imidazoä1,5aütriazoloä1,5dübenzodiazepin-derivative zur behandlung kognitiver störungen
WO2004111061A1 (fr) Imidazo[2,1-b]-1,3,4,-thiadiazole-2-sulfonamides acyles et non acyles, et utilisations associees
EP1150964B1 (fr) Pyrimidin-2,4(1h, 3h)-diones polycyliques ayant des restes alkyle fonctionnalises en position 1 et/ou 3, leur procede de production et preparations pharmaceutiques
WO2003089441A1 (fr) Mercaptans tricycliques, leur procede de production et leur utilisation
EP1319010B1 (fr) 2,3-dihydro-quinazolin-5-ones et 2,3-dihydro-benzo-[1,2,4]-thiadiazin-5,5-dioxydes substitues par un mercaptomethyle tricyclique et utilises comme inhibiteurs de la matrice metalloproteinase (mmp)
EP2007773B1 (fr) Thiazolyl-dihydro-indazoles
DE10101324C1 (de) 1-Dimercaptoalkylchinazolin-2,4-(1H,3H)-dione als Matrix-Metalloproteinase(MMP)-Inhibitoren
WO2003089416A1 (fr) Pyrimidine-2,4(1h,3h)-diones substituees en tant qu'inhibiteurs de la metalloproteinase matricielle (mmp)
TW201536795A (zh) 作為細胞保護劑用之芳基噻嗪化合物
EP1357114A1 (fr) Pyrimidine-2,4(1H,3H)-diones substituées en tant qu'inhibiteurs des matrix metalloprotéinases (MMP)
EP0640088B1 (fr) Nouveaux derives thiazoliques et thiaziniques tricycliques, et medicaments antiviraux contenant ces derives
EP0640087A1 (fr) Utilisation de derives de pyrimidine tricycliques comme medicaments antiviraux

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP