WO2004058747A1 - Fc receptor modulating compounds and compositions - Google Patents
Fc receptor modulating compounds and compositions Download PDFInfo
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- WO2004058747A1 WO2004058747A1 PCT/AU2003/001734 AU0301734W WO2004058747A1 WO 2004058747 A1 WO2004058747 A1 WO 2004058747A1 AU 0301734 W AU0301734 W AU 0301734W WO 2004058747 A1 WO2004058747 A1 WO 2004058747A1
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- alkyl
- independently selected
- aryl
- heteroaryl
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- 0 *C(c1c(*)c(*)c(*)c(*)c1*)=C(C(N1*)=O)SC1=S Chemical compound *C(c1c(*)c(*)c(*)c(*)c1*)=C(C(N1*)=O)SC1=S 0.000 description 3
- LXICTVYCSQLGTB-UHFFFAOYSA-N CC(C)OC(c([s]c1c2cccc1OC)c2OC(C)C)=O Chemical compound CC(C)OC(c([s]c1c2cccc1OC)c2OC(C)C)=O LXICTVYCSQLGTB-UHFFFAOYSA-N 0.000 description 1
- HZXHCDOZCRULSL-UHFFFAOYSA-N CC1(C=CC(OC)=CC11)SC(C(Cl)=O)=C1Cl Chemical compound CC1(C=CC(OC)=CC11)SC(C(Cl)=O)=C1Cl HZXHCDOZCRULSL-UHFFFAOYSA-N 0.000 description 1
- LZPNXAULYJPXEH-AATRIKPKSA-N COc1cc(/C=C/C(O)=O)ccc1 Chemical compound COc1cc(/C=C/C(O)=O)ccc1 LZPNXAULYJPXEH-AATRIKPKSA-N 0.000 description 1
- KVBWBCRPWVKFQT-UHFFFAOYSA-N OC(c1cc(I)ccc1)=O Chemical compound OC(c1cc(I)ccc1)=O KVBWBCRPWVKFQT-UHFFFAOYSA-N 0.000 description 1
- PCIDCTYXPGEFDP-UHFFFAOYSA-N OC(c1cccc(Sc2cc(C(O)=O)ccc2)c1)=O Chemical compound OC(c1cccc(Sc2cc(C(O)=O)ccc2)c1)=O PCIDCTYXPGEFDP-UHFFFAOYSA-N 0.000 description 1
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Definitions
- the invention relates to a novel class of Fc receptor modulating compounds. More particularly the present invention relates to a pharmaceutical composition comprising an Fc receptor modulating compound in combination with a pharmaceutically acceptable carrier.
- the immune system once triggered by a foreign organism, responds by generating a series of molecules, including molecules known as antibodies, which facilitate the destruction of the foreign organism.
- Autoimmune diseases are a group of disorders characterised by the failure of the immune system to distinguish between foreign and healthy tissue within the body.
- the immune system then generates antibodies to healthy or normal tissue including bones and joints (rheumatoid arthritis), platelets (immune thrombocytopenia purpura and blood vessels/ connective tissue (systemic lupus erythematosus).
- Antibodies produced by people suffering autoimmune diseases bind to healthy tissue resulting in formation of 'immune complexes'. These immune complexes bind to receptors on the surface of inflammatory white blood cells, called Fc receptors (FcR). When the immune complex binds to the FcR, white blood cells are activated releasing a series of chemicals known as cytokines into the blood system. These chemicals lead to the destruction of tissue and joints and also propagates the immune response so that attack on healthy tissue continues.
- Fc receptors Fc receptors
- Methotrexate non-specifically kills all dividing cells, eliminating the cells producing the antibodies.
- the major side effect of methotrexate is that it non-specifically kills cells of the immune system leaving the patient immuno- supressed.
- cytotoxic agents such as methotrexate.
- Methotrexate non-specifically kills all dividing cells, eliminating the cells producing the antibodies.
- the major side effect of methotrexate is that it non-specifically kills cells of the immune system leaving the patient immuno- supressed.
- a number of new products have been launched which inhibit the naturally produced chemicals that lead to tissue/joint destruction.
- the limitation of some of these products is that they target only one of the many inflammatory chemicals released. For example, Enbrel and Remicade inhibit the action of Tumour Necrosis Factor alpha ( INF) whilst Kineret inhibits Interleukin-1.
- the Fc receptor is a useful target for drug development because it is upstream in the inflammatory process and in theory, preventing the triggering of this receptor should block the release of many of the tissue-damaging chemicals.
- FcRs consist of a family of highly related receptors that are specific for the Fc portion of immunoglobulin (Ig).
- Receptors have been defined for each of the immunoglobulin classes and as such are defined by the class of Ig to which they bind (e.g. Fc gamma receptors (FcyR) bind gamma immunoglobulin (IgG), Fc epsilon receptors (Fc ⁇ R) bind epsilon immunoglobulin (IgB), Fc alpha receptors (Fc R) bind alpha immunoglobulin (IgA)).
- Fc gamma receptors FcyR
- Fc ⁇ R Fc epsilon receptors
- IgB epsilon immunoglobulin
- Fc R Fc alpha receptors
- Fc ⁇ RI which is a high affinity receptor for IgG
- Fc ⁇ RII which are low affinity receptors for IgG that bind to aggregates of immune complexes
- Fc ⁇ RIII which are low affinity receptors that bind to immune complexes. In recent times, further differentiation of these receptors has been achieved, such as, for example the identification of Fc ⁇ RIIa.
- Fc ⁇ RII Fc ⁇ RII
- Fc ⁇ R are expressed on most hematopoietic cells, and through the binding of IgG plays a key role in homeostasis of the immune system and host protection against infection.
- Fc ⁇ RII essentially binds only to IgG immune complexes and is expressed on a variety of cell types including, for example, monocytes, macrophages, neturophils, eosinophils, platelets and B lymphocytes.
- Fc ⁇ RII is involved in various immune and inflammatory responses including antibody-dependent cell mediated cytotoxicity, clearance of immune complexes, release of inflammatory mediators and regulation of antibody production.
- the binding of IgG to a Fc ⁇ R can lead to disease indications that involve regulation by Fc ⁇ R.
- thrombocytope ia purpura involves platelet damage resulting from Fc ⁇ R-dependent IgG immune complex activation of platelets or their destruction by Fc ⁇ R+ phagocytes.
- various inflammatory diseases including rheumatioid arthritis, and systemic lupus erythematosus involve IgG immune complexes.
- Fc ⁇ Rs exist at the surface of a cell. In essence, they are dimers of two virtually identical structures which meet in such as way that they define a groove. Structures of these dimers are disclosed in International Patent Application No. WO 99/40117. The Fc portion of aggregated antibody binds to this groove, hence compounds designed to interfere with the binding in the groove may inhibit antibody/ receptor binding.
- Suitable compounds are derived from random screening as well as rational drug design to modulate Fc receptors.
- Drug design depends at least in part on the structure of the site to which the compounds are intended to bind.
- US patent 6,355,683 has postulated the structure of the binding region of Fc ⁇ RIIa binding region based on X- ray crystallographic analysis. It is believed that the relevant binding site (that is, the groove) has a lip comprising lysine and histidine residues and represents a target for interaction with hydrogen-bonding and/ or acidic groups in a suitable modulator.
- the wall of the groove contains a p enylalanine benzene ring and may be a target for a hydrophobic interaction, particularly ⁇ - ⁇ interactions.
- the 'floor' of the groove includes Phel21, Thrl52, Leul59 and Serl ⁇ l and together with Asnl54, Lysll7 (backbone carbonyl) and Thr 119. These proteins are believed to be arranged to form a pocket that is capable of strong hydrogen bonding and /or Van der Waals interactions with a modulator or a ligand.
- FcRs are involved in a variety of biological mechanisms, it is important that the compounds identified as suitable for affecting the binding of immunoglobulins to Fc ⁇ R do not adversely affect the other biological functions of FcRs.
- US patent 6,355,683 discloses certain classes of aromatic, cyclic and amino acid species that modulate binding of immunoglobulins to Fc receptors.
- Fc receptor modulating compounds typically have a core lipophilic group, substituted with a group rich in ⁇ -electrons, preferably having a delocalised ⁇ -electron system.
- the compounds typically include at least one acidic group having a ⁇ -electron system.
- the present invention provides a compound capable of binding to a Fc receptor and modulating Fc receptor activity having the general formula I:
- Rl, R2, R3, R4, R5, are each independently selected from H, halogen, NO 2 , CN, C 1 . 6 alkyl, CF 3 , aryl, heterbaryl, cylcoalkyl, cycloheteroalkyl, OCF 3 , OR18, SR18, OC ⁇ . 6 alkyl, OC 2 - 6 alkylNR18R19, Oaryl, Oheteroaryl, Ocycloalkyl, Ocycloheteroalkyl, OC 1 - 6 alkylaryl, OC 1 - 6 alkylheteroaryl, O ⁇ alkylcycloalkyl, OC 1 .
- R18, R19 are each independently selected from H, C ⁇ alkyl, Q 1 alkyl cycloheteroalkyl, aryl, heteroaryl, C ⁇ alkyl aryl, C_._ alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- R20, R21 are each independently selected from H, Cj. 4 alkyl
- R6 is selected from H, C- ⁇ alkyl
- R7 is selected from H, C ⁇ alkyl, SH, CN;
- R8 is selected from OR9, NR9R10;
- R9, RIO are each independently selected from H, C ⁇ alkyl, C 1 . 4 alkylCO 2 H, C_ alkyl cycloheteroalkyl, aryl, heteroaryl, C 1 . 4 alkyl aryl, C-*- 4 alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR11;
- Rll is selected from H, ⁇ alkyl.
- the present invention provides a compound capable of binding to a Fc receptor and modulating Fc receptor activity having the general formula II:
- Rl, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are each independently selected from H, halogen, NO- ⁇ CN, C ⁇ . 6 alkyl, CF 3 , aryl, heteroaryl, cylcoalkyl, cycloheteroalkyl, OCF 3 , OR18, SR18, OC 1 . 6 alkyl, OC 2 . 6 alkylNR18R19, Oaryl, Oheteroaryl, Ocycloalkyl, Ocycloheteroalkyl, OC ⁇ alkylaryl, OC-,. 6 alkylheteroaryl, OC ⁇ .
- Rl ⁇ , R19 are each independently selected from H, C M alkyl, - 4 alkyl cycloheteroalkyl, aryl, heteroaryl, C- ⁇ alkyl aryl, - 4 alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- R20, R21 are each independently selected from H, C 1 - 4 alkyl
- Rll, R12 are each independently selected from H, C 1 - 4 alkyl, halogen, O ⁇ alkyl.
- the present invention provides a compound capable of binding to a Fc receptor and modulating Fc receptor activity having the general formula IE:
- Rl, R2, R3, R4, R5 and R6 are each independently selected from H, halogen, NO*-*, CN, C ⁇ . 6 alkyl, CF 3 , aryl, heteroaryl, cylcoalkyl, cycloheteroalkyl, OCF 3 , ORl ⁇ , SRl ⁇ , OQ- 6 alkyl, OC 2 - 6 alkylNR18R19, Oaryl, Oheteroaryl, Ocycloalkyl, Ocycloheteroalkyl, OC ⁇ .
- R18, R19 are each independently selected from H, - 4 alkyl, C*- 4 alkyl cycloheteroalkyl, aryl, heteroaryl, C*- 4 alkyl aryl, . 4 alkyl heteroaryl, or may be joined to form an optionally substituted 3- ⁇ membered ring optionally containing an atom selected from O, S, NR21;
- R20, R21 are each independently selected from H, C ⁇ - alkyl
- R7 is selected from H, C ⁇ alkyl, CF 3 , aryl, heteroaryl, cylcoalkyl, cycloheteroalkyl, CO 2 Rl ⁇ , C M alkylCO 2 Rl ⁇ , CONR18R19, - 4 alkylCONRl ⁇ R19, NRl ⁇ R19, C 1 . 6 alkylNRl ⁇ R19, NR20C 1 - 4 alkylNRl ⁇ R19, C 1 - 6 alkylNR20C ⁇ . 4 alkylNRl ⁇ R19, NRl ⁇ COR19, ⁇ alkylNR18COR19, C 1 - 6 alkylNR20CONR18R19,
- the present invention provides a compound capable of binding to a Fc receptor and modulating Fc receptor activity having the general formula IV:
- Rl, R2, R3, R4, R5 and R6 are each independently selected from H, halogen, NO-j, CN, -galkyl, CF 3 , aryl, heteroaryl, cylcoalkyl, cycloheteroalkyl, OCF 3 , ORl ⁇ , SRl ⁇ , OCj-galkyl, OC 2 - 6 alkylNRl ⁇ R19, Oaryl, Oheteroaryl, Ocycloalkyl, Ocycloheteroalkyl, OC ⁇ *.
- R18, R19 are each independently selected from H, . 4 alkyl, - 4 alkyl cycloheteroalkyl, aryl, heteroaryl, C 14 alkyl aryl, C ⁇ - 4 alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- R20, R21 are each independently selected from H, C ⁇ . 4 alkyl.
- the present invention provides a compound capable of binding to a Fc receptor and modulating Fc receptor activity comprising a core lipophilic group in the form of an Aryl ring substituted with a group rich in ⁇ -electrons.
- the present invention provides a pharmaceutical composition suitable for modulating Fc receptor activity in an animal comprising one or more compounds according to the first to fifth aspects of the present invention together with a pharmaceutically acceptable diluent.
- the present invention provides a method for treating an autoimmune disease involving Fc receptor activity comprising administering to a subject in need of treatment with a pharmaceutical composition according to the sixth aspect of the present invention.
- the present invention provides a method for obtaining a compound which modulates Fc receptor activity, the method comprising:
- the present invention provides a compound which modulates Fc receptor activity obtained by the method according to the eighth aspect of the present invention.
- the present invention provides a method for treating an autoimmune disease involving Fc receptor activity comprising administering to a subject in need of treatment with a pharmaceutical composition containing a compound which modulates Fc receptor activity according to the ninth aspect of the present invention.
- the present invention provides use of composition according to the sixth aspect of the present invention in treatment or therapies for autoimmune diseases involving Fc receptor activity.
- the present invention provides use of a compound according to the first to fifth aspects in the manufacture of a medicament for the treatment of an autoimmune disease.
- Fc receptor modulating compounds typically have a core lipophilic group, substituted with a group rich in ⁇ -electrons, preferably having a delocalised ⁇ -electron system.
- the compounds typically include at least one acidic group having a ⁇ -electron system.
- the present invention provides a compound capable of binding to a Fc receptor and modulating Fc receptor activity having the general formula I:
- Rl, R2, R3, R4, R5, are each independently selected from H, halogen, Oj, CN, - f -alkyl. CF 3 , aryl, heteroaryl, cylcoalkyl, cycloheteroalkyl, OCF 3 , OR18, SR18, OC w alkyl. OC 2 . 6 alkylNR18R19, Oaryl, Oheteroaryl, Ocycloalkyl, Ocycloheteroalkyl, OQ. 6 alkylaryl, OC ⁇ . 6 alkylheteroaryl, OQ-galkylcycloalkyl, OC ⁇ cycloheteroalkyl, C0 2 Rl ⁇ , C 1 .
- Rl ⁇ , R19 are each independently selected from H, C___ alkyl, Q- 4 alkyl cycloheteroalkyl, aryl, heteroaryl, C- ⁇ alkyl aryl, Q- 4 alkyl heteroaryl, or may be joined to form an optionally substituted 3- ⁇ membered ring optionally containing an atom selected from O, S, NR21;
- R20, R21 are each independently selected from H, C ⁇ - 4 alkyl
- R6 is selected fro H, C ⁇ alkyl
- R7 is selected from H, C- ⁇ alkyl, SH, CN;
- R ⁇ is selected from OR9, NR9R10
- R9, R10 are each independently selected from H, C-*_ 4 alkyl, C ⁇ . 4 alkylCO 2 H, C ⁇ - 4 alkyl cycloheteroalkyl, aryl, heteroaryl, C]. alkyl aryl, C**. 4 alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR11
- Rll is selected from H, C ⁇ alkyl.
- Rl, R2, R3, R4 and R5 are each independently selected from H, OH, OC- ⁇ alkyl, OC 1 . alkylaryl, ⁇ alkyl, halogen;
- R6 is selected from H, C ⁇ _ alkyl,
- R7 is selected from H, C ⁇ . 4 alkyl, SH, CN;
- R ⁇ is selected from OH, NR9R10;
- R9, R10 are each independently selected from H, C h alky!, C-*- 4 alkylCO 2 H.
- the present invention provides a compound capable of binding to a Fc receptor and modulating Fc receptor activity having the general formula II:
- Rl, R2, R3, R4, R5, R6, R7, R8, R9, and RIO are each independently selected from H, halogen, NO 2 , CN, - f -alkyl, CF 3 , aryl, heteroaryl, cylcoalkyl, cycloheteroalkyl, OCF 3 , ORl ⁇ , SRl ⁇ , OCj- ⁇ alkyl, OC 2 .
- Rl ⁇ , R19 are each independently selected from H, . 4 alkyl, - 4 alkyl cycloheteroalkyl, aryl, heteroaryl, C-*- 4 alkyl aryl, C ⁇ - alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- R20, R21 are each independently selected from H, C-*- alkyl
- Rll, R12 are each independently selected from H, ⁇ alkyl, halogen, OC ⁇ alkyl.
- Rl, R2, R3, R4, R5, R6, R7, R ⁇ , RIO are each independently selected from H, Q- 4 alkyl, OC 1 - 4 alkyl, CO 2 H, CN;
- Rll, R12 are each independently selected from H, Cj_ 4 alkyl.
- the present invention provides a compound capable of binding to a Fc receptor and modulating Fc receptor activity having the general formula III:
- Rl, R2, R3, R4, R5 and R6 are each independently selected from H, halogen, Oz, CN, Cj-galkyl, CF 3 , aryl, heteroaryl, cylcoalkyl, cycloheteroalkyl, OCF 3 , ORl ⁇ , SR18, O -ealkyl, OC 2 - 6 alkylNR18R19, Oaryl, Oheteroaryl, Ocycloalkyl, Ocycloheteroalkyl, O -ealkylaryl, O -ealkylheteroaryl, OC 1 - 6 alkylcycloalkyl, O - ⁇ cycloheteroalkyl, CO 2 Rl ⁇ , -galkylCO-jRl ⁇ , CONR16R19, C ⁇ alkylCONRl ⁇ Rl ⁇ NRl ⁇ R19, C ⁇ .
- R18, R19 are each independently selected from H, C H alkyl, C M alkyl cycloheteroalkyl, aryl, heteroaryl, ⁇ alkyl aryl, - 4 alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- R20, R21 are each independently selected from H, C ⁇ . 4 alkyl
- R7 is selected from H, C-*- 6 alkyl, CF 3 , aryl, heteroaryl, cylcoalkyl, cycloheteroalkyl, CO 2 R18, C w alkylCO ⁇ R18. CONR18R19, C M alkylCO R18R19. NR18R19, C ⁇ alkylNRl ⁇ RW, NR20C ⁇ . 4 alkylNR18R19, ⁇ alkylNRZO ⁇ alkylNRl ⁇ RW.
- NR18COR19 - 6 alkylNR18COR19, - ⁇ alkylNRMCONRl ⁇ RW, NR20CONR18R19, Cj- ⁇ alkylNRl ⁇ SOzRig, NRl ⁇ SO 2 R19 wherein Rl ⁇ , R19 are as defined above.
- Rl, R2, R3, R4, R5, and R6 are each independently selected from H, halogen, OH,
- R7 is selected from H, C ⁇ a-kyl, - 4 alkylCO 2 H.
- the present invention provides a compound capable of binding to a Fc receptor and modulating Fc receptor activity having the general formula IV:
- Rl, R2, R3, R4, R5 and R6 are each independently selected from H, halogen, NO-j, CN, C; ⁇ -,alkyl, CF 3 , aryl, heteroaryl, cylcoalkyl, cycloheteroalkyl, OCF 3 , ORl ⁇ , SR18, OC- K -alkyl, OC 2 - 6 alkylNR18R19, Oaryl, Oheteroaryl, Ocycloalkyl, Ocycloheteroalkyl, OC ⁇ - 6 alkylaryl, OQ- 6 alkylheteroaryl, OC ⁇ - 6 alkylcycloalkyl, OC ⁇ cycloheteroalkyl, C0 2 R18, C 1 - 6 alkylCO 2 Rl ⁇ , CONRl ⁇ R19, C 1 ⁇ alkylCONR18R19 / NR18R19, C w alkylNR18R19, NR20C 1 .
- Rl ⁇ , R19 are each independently selected from H, C w alkyl, Q- 4 alkyl cycloheteroalkyl, aryl, heteroaryl, C 1 - 4 alkyl aryl, C ⁇ - alkyl heteroaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR21;
- R20, R21 are each independently selected from H, C-*- alkyl.
- Rl, R2, R3, R4 are each independently selected from H, halogen, NO*>, OC ⁇ alkyl, C M alkyl;
- R5 is selected from H, Cl, O ⁇ alkyl, O ⁇ alkylaryl, OC 3 . 6 cycloalkyl;
- R6 is selected from CO 2 H, CONR 7 R 8 ;
- R7, R8 are each independently selected from H, 5-tetrazole.
- alkyl means an unsubstituted or optionally substituted straight or branched alkyl chain.
- Aryl means unsubstituted or optionally substituted phenyl or naphthyl.
- Heteroaryl means an unsubstituted or optionally substituted 5 ⁇ or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N, S.
- Cycloalkyl means an optionally substituted 3-8 membered saturated ring.
- Cycloheteroalkyl means an optionally substituted 3-8 membered saturated ring containing 1-3 heteroatoms selected from O, S, NR24, where R24 is H, C-,_ 4 alkyl, aryl, heteroaryl.
- the present invention provides a compound capable of binding to a Fc receptor and modulating Fc receptor activity comprising a core lipophilic group in the form of an Aryl ring substituted with a group rich in ⁇ -electrons.
- the substituent on the Aryl ring comprises a 5 or 6 membered ring system having ⁇ bonds and /or a carbon chain comprising, or substituted with heteroatoms having ⁇ electrons.
- the substituted Aryl ring is selected from:
- Rl is selected from the group -COOH, -COOCHg, -N0 2 -OCH 3 -OH, -CN, halides and hydrogen,
- R2 is selected from the group -NO*-,, -COOH, halides and hydrogen;
- X is selected by the group -S(O)Ar(COOH), -S(CH 2 ) 3 CN, -C(O)CH 2 SAr(COOH),
- the aromatic compound may be, for example, a substituted Aryl ring (Ar) selected from:
- Rl is -COOH, located at position 3 on the aryl ring and R2 is hydrogen;
- Rl is -NO z located at position 6 on the aryl ring and R2 is hydrogen;
- Rl is -OCH 3 located at position 5 on the aryl ring and R2 is hydrogen;
- Rl is -OCH 3 located at position 7 on the aryl ring and R2 is hydrogen;
- Rl and R2 are -NO 2 located at positions 3 and 5 on the aryl ring; when X is the fused heteroatomic fused ring system
- Rl is -OCH 3 located at position 5 on the aryl ring and R2 is -NO 2 located at position 4 on the aryl ring;
- Rl is -COOH located at position 2 on the aryl ring and R2 is hydrogen;
- Rl is COOH located at position 4 on the aryl ring and R2 is hydrogen;
- Rl is -CN or H located at position
- Rl is -COOCH 3 located at position 3 on the aryl ring and R2 is hydrogen;
- Rl and R2 are -Cl located at positions 3 and 5 on the aryl ring.
- the compound is selected from compounds [197], [216], [217], [238], [239], [261], [294], [297] and [299]. More preferably the compound is selected from [197] and [294].
- the present invention provides a pharmaceutical composition suitable for modulating Fc receptor activity in an animal comprising one or more compounds according to the first to fifth aspects of the present invention together with a pharmaceutically acceptable diluent.
- the present invention provides a method for treating an autoimmune disease involving Fc receptor activity comprising administering to a subject in need of treatment with a pharmaceutical composition according to the sixth aspect of the present invention.
- the present invention provides a method for obtaining a compound which modulates Fc receptor activity, the method comprising:
- step (a) comprises functionalising the compounds with one or more substituent groups.
- the compounds are screened by a Fc ⁇ RIIa dependent platelet activation assay and/ or aggregation assay where platelets are activated using heat aggregated human immunoglobulin G as an immune complex.
- the compounds can be tested in a collagen-arthritis model in Fc ⁇ RIIa transgenic animals.
- Such a model is disclosed, for example, in PCT/ AU03/00718 entitled "Transgenic Animal Model for Autoimmune Disease" in the name of Arthron Ltd.
- the compounds may be screened by measuring the inhibition of an Fc receptor to a ligand in an ELISA based system.
- the receptor is Fc ⁇ receptor
- the ligand used may be selected from heat aggregated IgG (HAGG) or monomeric IgG or the like.
- the present invention provides a compound which modulates Fc receptor activity obtained by the method according to the eighth aspect of the present invention.
- the present invention provides a method for treating an autoimmune disease involving Fc receptor activity comprising administering to a subject in need of treatment with a pharmaceutical composition containing a compound which modulates Fc receptor activity according to the ninth aspect of the present invention.
- the present invention provides use of composition according to the sixth aspect of the present invention in treatment or therapies for autoimmune diseases involving Fc receptor activity.
- the present invention provides use of a compound according to the first to fifth aspects in the manufacture of a medicament for the treatment of an autoimmune disease.
- the autoimmune disease involves aggregates of antibodies are produced or where immune complexes are produced by contact of antibody with intrinsic or extrinsic antigen causing damage to normal tissue of an individual.
- modulation of Fc receptors by the above identified compounds is used to treat a disease where aggregates of antibodies are produced or where immune complexes are produced by contact of antibody with intrinsic or extrinsic antigen. Modulation of Fc receptors by the above identified compounds can also be used to reduce IgG-mediated tissue damage, to reduce IgE-mediated response and/ or to reduce inflammation in a patient.
- the present invention provides a variety of compounds which can modulate the interaction between Fc receptors and immunoglobulins. Without wishing to be bound by theory it is believed that these compounds interfere with the groove, or dimerization interface between two Fc ⁇ RII proteins, thereby affecting cellular signal transduction through one or both of the FcR proteins. Specifically, it is believed that peptide residues 117-131 and 150-164 of Fc ⁇ RII make up the interfacial area of the Fc ⁇ RIIa dimer, and the compounds of the present invention may mimic or bind to these regions and thus have activity as good binding modulators.
- the compounds of the present invention can provide strong ⁇ - ⁇ interaction and /or hydrogen-bonding with the wall of the groove while the hydrogen bonding an/ or acidic groups interact with the amino acid residues at the lip and floor of the groove.
- Compounds of the invention may also bind to other regions of the receptor, as indicated by computer modelling or "docking". For example, some compounds may bind to the FG loop of the Fc ⁇ receptor, or to areas around tryptophan residues such as Trp90 or Trp 113.
- the scope of this invention includes isomers of the relevant compounds and mixtures thereof.
- compounds of the present invention having chiral centres may be synthesised enantioselectively or a mixture of enantiomers and/ or diastereomers can be prepared and separated. The resolution of the diasteromers may be carried out by any procedure known in the art.
- the compounds of the present invention contain an olefin moiety which can be either of cis- or trans- configuration, the compounds can be synthesized to produce ⁇ ' s- or foan-s-olefin selectively as the predominant product.
- the compounds containing an olefin moiety can be produced as a mixture of cis- and tra ⁇ s-olefins and separated using known, procedures.
- the compounds of the present invention may form salts with acids when a basic functional group is present and salts with bases when an acid functional group is present. All such salts are useful in the isolation and /or purification of the new compounds. Of particular value are the pharmaceutically acceptable salts with both acids and bases. Suitable acids include, for example hydrochloric, oxalic, sulphuric, nitric, benzenesulphonic, toluenesulphonic, acetic, maleic, tartaric and the like which are pharmaceutically acceptable.
- Basic salts for pharmaceutical use include sodium, potassium, calcium and magnesium salts.
- the compounds of the present invention are preferably selected according to the following protocol:
- the compounds of Table 1 were screened in a Fc ⁇ RIIa dependent platelet activation assay and /or aggregation assay where platelets are activated using heat aggregated human immunoglobulin G as an immune complex. Compounds inhibiting this process were then tested for specificity. Note that the platelets were used as the target as the only Fc receptor expressed on these cells is Fc ⁇ RIIa. In addition, they are very difficult to inhibit and therefore this assists in identifying compounds with reasonable potency. The compounds may also be screened using an ELISA inhibition assay to detect the blockade of IgG interaction with Fc ⁇ RIIa.
- the compounds were tested for activity against other platelet activation pathways. These were principally induced by arachidonic acid and/ or ADP - some of these compounds have also been tested for their capacity to inhibit collagen and/ or thrombin induced platelet activation.
- the specific inhibitory compounds were then titrated in the platelet activation assay.
- Table 2 depicts the compounds that displayed the most promising activities.
- the compounds of the present invention modulate Fc receptors selected from the group consisting of FcoR, Fc ⁇ R, Fc ⁇ R, and mixtures thereof, more preferably from the group consisting of Fc ⁇ RIIa, Fc ⁇ RIIb, Fc ⁇ RIIb, Fc ⁇ RIIc and mixtures thereof and most preferably the Fc ⁇ RIIa receptor.
- Fc receptors selected from the group consisting of FcoR, Fc ⁇ R, Fc ⁇ R, and mixtures thereof, more preferably from the group consisting of Fc ⁇ RIIa, Fc ⁇ RIIb, Fc ⁇ RIIb, Fc ⁇ RIIc and mixtures thereof and most preferably the Fc ⁇ RIIa receptor.
- the compounds of the present invention can be used in a variety of applications including treatment or diagnosis of any disease where aggregates of antibodies are produced and where immune complexes are produced by contact of antibody with intrinsic or extrinsic antigen.
- Exemplary treatments and diagnosis applicable by the compounds of the present invention include immune complex diseases; autoimmune diseases including but not limited to rheumatoid arthritis, systemic lupus erythematosus, immune thrombocytopenia, neutropenia, hemolytic anaemias; vasculities including but not limited to polyartheritis nodosa, systemic vasculitis; xenograft rejection; and infectious diseases where FcR uptake of virus enhances infection including but not limited to flavivirus infections such as Dengue virus-dengue hemorrhagic fever and measles virus infection.
- the compounds of the present invention can also be used to reduce IgG mediated tissue damage and to reduce inflammation.
- the compounds of the present invention can also enhance leukocyte function by enhancing FcR function.
- FcR function include antibody dependent cell mediated cytotoxicity, phagocytosis, release of inflammatory cytokines.
- Exemplary treatments and diagnosis for enhanced FcR function include any infection where normal antibodies are produced to remove the pathogen; and any disease requiring FcR function where natural or recombinant antibodies can be used in treatment such as cancer and infections, for example the antibody can be administered in combination with the compound of the present invention to enhance the effect of the antibody treatment.
- the compounds of the present invention can be administered to a patient to achieve a desired physiological effect.
- the patient is an animal, more preferably a mammal, and most preferably a human.
- the compound can be administered in a variety of forms adapted to the chosen route of administration, that is, orally or parenterally.
- Parenteral administration includes administration by the following routes: intravenous; intramuscular; subcutaneous; intraocular; intrasynovial; transepithelially including transdermal, ophthalmic, sublingual and buccal; topically including opthalmic, dermal, ocular, rectal and nasal inhalation via insufflation and aerosol; intraperitoneal; and rectal systemic.
- the active compound can be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it can be enclosed in hard or soft shell gelatin capsules, or it can be compressed into tablets, or it can be incorporated directly with the food of the diet.
- the active compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixers, suspensions, syrups, wafers, and the like.
- compositions and preparations can contain any therapeutically effective amount of active compound.
- the tablets, troches, pills, capsules and the like can also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatine; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin can be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring.
- a binder such as gum tragacanth, acacia, corn starch or gelatine
- excipients such as dicalcium phosphate
- a disintegrating agent such as corn starch, potato starch, alginic acid and the like
- a lubricant such as magnesium stearate
- a sweetening agent such as sucrose, lactose or saccharin can be added or a flavouring agent such as
- tablets, pills or capsules can be coated with shellac, sugar or both.
- a syrup or elixir can contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour.
- any material used in preparing any dosage unit form should be pharmaceutically pur and substantially non-toxic in the amounts employed.
- the active compound can be incorporated into sustained-release preparations and formulations.
- the active compound can also be administered parenterally.
- Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
- dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the form must be sterile and must be fluid to the extent that easy syringability exists. It can be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent of dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of surfactants.
- microorganisms can be brought bout by various antibacterial and antifungal agents, for example, parabens, chlorbutanoL phenol, sorbic acid, thimerosal and the like.
- isotonic agents such as sugars or sodium chloride.
- Prolonged absorption of the injectable compositions of agents delaying absorption such as aluminium monostearate and gelatin.
- Sterile injectable solutions are prepared by incorporating the active compound in the require amount in the appropriate solvent with various other ingredients as required, followed by filtered sterilisation.
- dispersions are prepared by incorporating the various sterilised active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients.
- sterile powders for the preparation of sterile injectable solutions the preferred drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
- the therapeutic compounds of the present invention can be administered to a mammal alone or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.
- the compounds may also be co-administered with other agents such as methotrexate, Enbrel, Ramicade, Kinaret or the like.
- Figure 1(a) is a graph of % Inhibition (p-selectin loss) against dosage level, illustrating inhibition of IgG induced platelet activation as a function of dose responses using FACS;
- Figure Kb is a graph depicting inhibition of Platelet Aggregation by compound [153] as a function of time ( in minutes);
- Figure 2(a) is a graph of Arthritis Index as a function of time (in days) for treatment of Fc ⁇ RIIa transgenic mice with compound [153] using four different dosage regimes, as compared with phosphate buffered saline (PBS);
- PBS phosphate buffered saline
- Figures 2(b) to (d) which depict the individual dosage regimes of Figure 2(a) with error bars, as compared with PBS;
- Figure 3 is a graph of Arthritis Index against time in Days for treatment of control mice (non-transgenic mice) with compound [153] as compared with PBS;
- Figure 4 is a graph of % Inhibition of IgG induced platelet activation against compound Concentration (mM) for some of the compounds of the present invention
- Figure 5 is a graph of % Inhibition of Platelet Activation against compound Concentration (mM) for further compounds of the present invention
- Figure 6 is a graph of % Inhibition of Platelet Activation against compound Concentration (mM) for compounds VIB 238, 239 and 197 of the present invention.
- the compounds of the present invention were selected on the basis of their in vitro and in vivo activity as follows;
- the compounds of the present invention were initially screened in a rapid FACS screening assay, measuring activation of human platelets by heat aggregated IgG.
- Platelets have only one type of Fc ⁇ receptor, Fc ⁇ RIIa, hence the use of human platelets eliminated the confounding effects of other Fc ⁇ receptors.
- platelets are very sensitive to a range of stimuli and activate rapidly. Activation is measured by the appearance of the protein P-Selectin on the platelet membrane after exposure to various stimuli.
- the stimuli were heat aggregated with IgG and as specificity controls, collagen or thrombin.
- this assay utilises washed platelets and heat aggregated IgG (HAGG) as an immune complex (agonist) to activate and crosslink Fc ⁇ RIIa. Because this is a primary screen a single concentration of small molecule inhibitor is added to the platelets (final concentration of 500 ⁇ g/ml) and allowed to incubate for 30 minutes. Heat Aggregated IgG (HAGG) (40 ⁇ g/ml) is then added to the platelets and allowed to incubate for 30 minutes. Paraformaldehyde is added to the platelets for 30 minutes prior to washing.
- HAGG heat aggregated IgG
- the specificity assay compares the effects of the small molecule inhibitors on HAGG (Fc ⁇ RIIa) activation and the unrelated activation by arachidonic acid, ADP and /or thrombin which are potent stimulators of platelets. This assay also indicates that the small molecule inhibitor has not killed the platelets.
- washed platelets 400 ⁇ l are incubated in the presence of a range of concentrations of small molecule inhibitor.
- the agonist eg HAGG (200 ⁇ g/ml) is then added and aggregation measured in an aggregometer, as described by others (Ozaki, Y.; 1998, Sysmex Journal International 8:15; Gratacap M. P. et al; Blood 96:3439 and Gross B.S. et al (1999) Blood 94:4166).
- the activity was measured as a function of inhibition of platelet activation and /or platelet aggregation as detailed above. Specificity is defined as specific inhibition of immune complex induced platelet activation but with no effect on arachidonic acid induced activation (and where tested no effect on thrombin, collagen or ADP induced activation).
- HSA-Fc ⁇ RIIa Human Serum Albumin genetically fused to Fc ⁇ RIIa
- HSA-Fc ⁇ RIIa Human Serum Albumin genetically fused to Fc ⁇ RIIa
- the small molecule inhibitors were titrated from a starting concentration of 5mg/ml and allowed to incubate in the presence of the receptor.
- a human IgG complex (0.2 ⁇ g/ml) is then added to the plate and the extent of inhibition of IgG binding by the small molecule inhibitors was measured using HRP labelled anti- human antibody.
- mice Genetically engineered mice were used to test the interaction of the compounds of the present invention with the human form of the Fc ⁇ RIIa prior to clinical studies.
- the mice used have the human form of Fc ⁇ RIIa genetically inserted into their DNA so that the mice produce human receptors on the surface of their inflammatory white blood cells and platelets.
- the mice used were C57BL/6/SJL, H-2b inbred mice expressing the Fc ⁇ RIIa transgene on platelets, neutrophils and macrophages at physiological levels.
- the severity of arthritis in mice was considerably greater in the Fc ⁇ RIIa transgenic mice than in normal control mice that do not express the receptor.
- Collagen-induced arthritis was chosen as a suitable model for testing the in vivo activity of a selection of compounds of the present invention.
- Mice were immunised with collagen, and boosted 21 days later at which time they were given the first dose of one of the compounds.
- the induction of arthritis using collagen was carried out according to the well described methods (Campbell, Bendele et al, 1997, Ann. Rheum. Dis.56(6): 364-8).
- An emulsion is formed by combining 2 mg/ml chicken collagen type II dissolved in 10 mM acetic acid in an equal volume of Complete Freund's Adjuvant. One hundred microlitres of the emulsion was injected intradermally at the base of the tail. The same dose was prepared and administered proximal to the primary site 21 days later.
- a standard arthritis scoring system index was used to measure the severity of the disease for the duration of the treatment period (up to 60 days).
- the mice were examined 3 times per week from day 14 to 36 after the first collagen injection.
- the severity of arthritis was rated on a scale from 0 to 3 for each limb based on the swelling, redness and joint function.
- the score (arthritis index) for each mouse was calculated as the sum of the score from the four limbs according to the following:
- Score 3 severe swelling and redness accompanied by joint dysfunction.
- Figure 2(a) is a graph of Arthritis Index against time (in days) for treatment of Fc ⁇ RIIa transgenic mice with compound [153] as compared with treatment with PBS. The mice were tested between 12 to 14 weeks of age with compound [153] according to abovementioned dosage Regimes 1 to 4. By comparison with the PBS dosing regime, all the dosage regimes were successful, Regime 1 being comparatively more effective than Regimes 1, 2 or 3.
- Figures 2(b) to 2(e) depict each of the individual dosage regimes depicted in Figure 2(a) with the addition of error bars.
- Figure 3 is a graph of Arthritis Index against time in Days for treatment of control (non- transgenic) mice with compound [153].
- the mice were tested between 12 to 14 weeks of age with compound [153] according to abovementioned dosage Regimes 3 and 4.
- the compound does not have a significant effect in non-transgenic mice implying specificity of action. Mice that have been treated in this way do not develop more severe arthritis upon cessation of treatment.
- Figure 4 is a graph of % Inhibition of IgG induced platelet activation against compound Concentration (mM) for nine of the compounds of the present invention, namely [216], [217], [261], [292], [294], [297], [299], [153] and [197].
- the compounds were titrated and evaluated for capacity to prevent aggregated IgG induction of p-selectin expression as a measure of activation.
- Figure 5 is a graph of % Inhibition of Platelet Activation against compound Concentration ( M) for three of the compounds of the present invention, namely [113], [152] and [153].
- Figure 6 is a graph of % Inhibition of Platelet Activation against compound Concentration (mM) for four of the compounds of the present invention, namely [238], [239], [197] and [153].
- Figures 4 to 6 showing the in vitro dose responses are, for the most part, only those compounds that have been through the entire selection program to the point where they would be ready for testing in vivo.
- Isopropanol (2.0 mL) was added to a suspension of sodium hydride (60 % dispersion, 110.0 mg, 2.75 mmol) and the reaction mixture was stirred at room temperature for 90 minutes.
- Isopropyl 3-chloro-7-methoxy-l-benzo[b]thiophene-2-carboxylate (400.0 mg, 1.4 mmol) was dissolved in anhydrous THF (2.0 mL) and the solution was added to the sodium hydride suspension and the resulting reaction mixture was heated to reflux for 17 hours. The reaction mixture was allowed to cool and the reaction mixture was concentrated under reduced pressure. The resulting residue was partitioned between hexane and water.
- 3-Isopropoxy-5-methoxy-l-benzo[b]thio ⁇ hene-2-carboxylic acid (200.0 mg, 0.75 mmol) was added to acetic acid (5.0 mL) and concentrated nitric acid (1.0 mL) and the reaction mixture was stirred at between 0 and 5°C in an icebath for 66 minutes.
- Rhodanine (2.0 g, 15.0 mmol), was added to a stirred solution of ammonium acetate (120.0 mg) and glacial acetic acid (360.0 L) in benzene (13.0 L). The reaction mixture was stirred to boiling for 5 minutes. 3-Hydroxyacetophenone (2.0 g, 145.7 mmol) was then added to the reaction mixture and the flask was connected to a Dean Stark trap. The reaction mixture was then heated to reflux overnight, then allowed to cool to room temperature after which a yellow precipitate formed. The precipitate was then collected by filtration, washed with water and purified by recrystallisation from (methanol/ water) to afford (2.17 g, 59.0 %) of the desired product as a yellow powder.
- the nitrile (VIB 216) (100 mg, 0.316 mmole) was dissolved in acetic acid (3 ml), cone sulphuric acid (1 ml) and water (1 ml) and the mixture refluxed overnight. A precipitate formed overnight. The mixture was added to water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried and evaporated to yield the product
- Rhodanine-3-acetic acid (2.81 g, 14.7 mmol) was added to a stirring solution of ammonium acetate (120.0 mg) and glacial acetic acid (360.0 L) in anhydrous benzene (30.0 mL). The reaction mixture was stirred to boiling for 5 minutes. 3-Hydroxyacetophenone (2.0 g, 14.7 mmol) was then added to the reaction mixture and the flask was connected to a Dean Stark trap.
- reaction mixture was then heated to reflux overnight, then allowed to cool to room temperature after which the solvent was evaporated under reduced pressure to afford a orange /red gum, which was purified with column chromatography eluting with (chloroform /methanol /acetic acid) (95/5/10 drops) to afford the desired 5-(-methyl-3-hydroxybenzylidine) rhodanine-3-acetic acid as a viscous red oil.
- column chromatography eluting with (chloroform /methanol /acetic acid) (95/5/10 drops) to afford the desired 5-(-methyl-3-hydroxybenzylidine) rhodanine-3-acetic acid as a viscous red oil.
- aqueous phase was then acidified with concentrated hydrochloric acid to produce a white precipitate which was isolated by filtration and washed with water, then dried to afford (544.0 mg, 66.8 %) of the desired 4-phenethyloxycinnamic acid as a white powder.
- reaction mixture was then allowed to cool to approximately 40 °C and another batch of potassium tertiarybutoxide (3.7 g, 32.9 mmol) was added and the reaction mixture was allowed to heat to reflux for 20 hours, aqueous 2.5 ⁇ sodium hydroxide (30.0 mL) was added and the reaction mixture was heated to reflux overnight. The reaction mixture was allowed to cool and the methanol was evaporated under reduced pressure to afford a white residue which was taken up in water and the aqueous solution was acidified with concentrated hydrochloric acid and a pink solid precipitated and was collected by filtration.
- Methyl 3-benzyloxy-l-benzo[b]thiophene-2-carboxylate (1.5 g, 5.0 mmol) was dissolved in methanol (50.0 L) and aqueous 2.5N sodium hydroxide (30.0 mL) was added and the reaction mixture was heated to reflux overnight. The reaction mixture was allowed to cool and the methanol was evaporated under reduced pressure to afford a white residue which was taken up in water and the aqueous solution was acidified with concentrated hydrochloric acid and a pink solid precipitated and was collected by filtration.
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JP2004562392A JP2006516133A (en) | 2002-12-24 | 2003-12-24 | Fc receptor modulating compounds and compositions |
CA002511356A CA2511356A1 (en) | 2002-12-24 | 2003-12-24 | Fc receptor modulating compounds and compositions |
EP03767317A EP1585745A4 (en) | 2002-12-24 | 2003-12-24 | Fc receptor modulating compounds and compositions |
US12/024,859 US7910770B2 (en) | 2002-12-24 | 2008-02-01 | Fc receptor modulating compounds and compositions |
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Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3869553A (en) * | 1972-11-07 | 1975-03-04 | Pfizer | Substituted benzoic acid hypolipemic agents |
BE854857A (en) * | 1976-05-21 | 1977-11-21 | Serdex Soc D Etudes De Rech S | NEW ACETOPHENONE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS |
DE3532280A1 (en) * | 1985-09-11 | 1987-03-12 | Bayer Ag | Sulphur-containing substituted carbonyl compounds |
EP0211670B1 (en) * | 1985-08-09 | 1990-05-09 | Eli Lilly And Company | Di-t-butylphenol compounds |
WO1995002406A2 (en) * | 1993-07-15 | 1995-01-26 | Warner-Lambert Company | Use of benzothiophenes and benzofurans for the treatment of inflammatory bowel disease and inflammation assay method |
WO1995015323A1 (en) * | 1993-12-03 | 1995-06-08 | Warner-Lambert Company | IMPROVED PROCESS FOR THE SYNTHESIS OF 3-CHLOROBENZO[b]THIOPHENE-2-CARBONYL CHLORIDES |
EP0722729A2 (en) * | 1995-01-23 | 1996-07-24 | Eli Lilly And Company | Aryl-substituted rhodanines for treating multiple sclerosis |
EP0621255B1 (en) * | 1993-04-20 | 1997-08-20 | Adir Et Compagnie | Substituted phenoxy-isobutyric acids and esters |
EP0434394B1 (en) * | 1989-12-21 | 1998-08-05 | Eli Lilly And Company | Compounds for treating inflammatory bowel disease |
EP0920862A1 (en) * | 1997-11-14 | 1999-06-09 | Eli Lilly And Company | 2-Arylbenzo b thiophenes useful for the treatment of estrogen deprivation syndrome |
WO2000015214A1 (en) * | 1998-09-11 | 2000-03-23 | Ilexus Pty Limited | Fc RECEPTOR MODULATORS AND USES THEREOF |
WO2001025193A1 (en) * | 1999-10-04 | 2001-04-12 | Nippon Soda Co., Ltd. | Phenolic compounds and recording materials containing the same |
WO2002042289A2 (en) * | 2000-11-27 | 2002-05-30 | Eli Lilly And Company | Process for preparing 3-aryl-benzo[b]thiophenes |
JP2003055340A (en) * | 2001-08-10 | 2003-02-26 | Daikin Ind Ltd | alpha,alpha-DIFLUOROSULFIDE COMPOUND, alpha,alpha-DIFLUOROSULFOXIDE COMPOUND AND alpha,alpha-DIFLUOROSULFONE COMPOUND |
JP2003252794A (en) * | 2002-03-01 | 2003-09-10 | Ono Pharmaceut Co Ltd | Apoptosis inhibitor containing aldose reductase inhibitor as active ingredient |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3855285A (en) * | 1971-06-21 | 1974-12-17 | Pfizer | Acylmethylthio-trifluoromethyl-benzoic acids |
JPS51125736A (en) * | 1974-12-03 | 1976-11-02 | Rikagaku Kenkyusho | An insecticide for agriculture and gardening |
DE3361275D1 (en) * | 1982-05-04 | 1986-01-02 | Lipha | Sustained-release theophyllin drug formulation |
JPS6156175A (en) * | 1984-08-24 | 1986-03-20 | Yamanouchi Pharmaceut Co Ltd | Rhodanine derivative and its preparation |
GB8729109D0 (en) * | 1987-12-14 | 1988-01-27 | Greig Smith P W | Improvements in/relating to avian control |
JPH03275657A (en) * | 1989-07-05 | 1991-12-06 | Kanegafuchi Chem Ind Co Ltd | Cinnamic acid amide derivative |
CA2012634A1 (en) * | 1990-03-20 | 1991-09-20 | Hassan Salari | Tyrphostins for treatment of allergic, inflammatory and cardiovascular diseases |
US5554767A (en) * | 1993-05-21 | 1996-09-10 | Warner-Lambert Company | Alpha-mercaptoacrylic acid derivatives having calpain inhibitory activity |
JPH0892191A (en) * | 1994-09-26 | 1996-04-09 | Terumo Corp | Hydroxamic acid derivative and pharmaceutical preparation containing the derivative |
JPH10147568A (en) * | 1996-11-19 | 1998-06-02 | Mitsui Chem Inc | Naphthalene derivative and medicine containing the same as active ingredient |
JPH10245357A (en) * | 1997-03-03 | 1998-09-14 | Yakult Honsha Co Ltd | Phenylpropenone and medicine containing the same |
ATE294158T1 (en) * | 1997-05-14 | 2005-05-15 | Atherogenics Inc | A MONOETHER OF PROBUCOL AND METHODS OF INHIBITING VCAM-1 EXPRESSION |
KR20010024899A (en) | 1998-02-06 | 2001-03-26 | 일렉서스 피티와이 리미티드 | Three dimentional structures and models of Fc receptors and uses thereof |
TWI262185B (en) * | 1999-10-01 | 2006-09-21 | Eisai Co Ltd | Carboxylic acid derivatives having anti-hyperglycemia and anti-hyperlipemia action, and pharmaceutical composition containing the derivatives |
US6469063B1 (en) * | 1999-11-18 | 2002-10-22 | City Of Hope | Inhibition of inflammation via inhibition of COX-2 gene transcription |
EP1287363A2 (en) * | 2000-05-25 | 2003-03-05 | Sunol Molecular Corporation | Modulation of t-cell receptor interactions |
CA2414464A1 (en) * | 2000-06-29 | 2002-01-10 | Abbott Laboratories | Aryl phenycyclopropyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents |
FR2818128B1 (en) * | 2000-12-18 | 2004-04-02 | Oreal | ANTISOLAR COSMETIC COMPOSITIONS BASED ON A SYNERGETIC MIXTURE OF FILTERS AND USES |
DE60119378T8 (en) * | 2000-12-27 | 2007-03-29 | Pola Chemical Industries, Inc. | BENZOFURAN DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US6774116B2 (en) * | 2001-04-17 | 2004-08-10 | Cryolife, Inc. | Prodrugs via acylation with cinnamate |
AU2002364549B2 (en) * | 2001-12-10 | 2007-11-22 | Amgen, Inc | Vanilloid receptor ligands and their use in treatments |
BR0308837A (en) * | 2002-04-01 | 2005-02-01 | Cadila Healthcare Ltd | Compound, composition, method and medicament for the treatment of bacterial infections, psoriasis or arthritis in mammals, method and medicament for the treatment of chemotherapy toxicity in a patient, pharmaceutical composition, process for preparing a compound and process for conversion of the compounds of formula (i) into additional compounds of formula (i) |
NZ536963A (en) | 2002-06-07 | 2008-04-30 | Trillium Therapeutics Inc | Use of the discovery that Fc gamma receptor IIA transgenic animals are susceptible to autoimmune disease, to suppress aberrant immune activity and to treat or prevent autoimmune disease |
AU2002953533A0 (en) * | 2002-12-24 | 2003-01-16 | Arthron Limited | Fc receptor modulating compounds and compositions |
-
2002
- 2002-12-24 AU AU2002953533A patent/AU2002953533A0/en not_active Abandoned
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2003
- 2003-12-24 US US10/541,045 patent/US7332631B2/en not_active Expired - Fee Related
- 2003-12-24 JP JP2004562392A patent/JP2006516133A/en active Pending
- 2003-12-24 AU AU2003291859A patent/AU2003291859A1/en not_active Abandoned
- 2003-12-24 WO PCT/AU2003/001734 patent/WO2004058747A1/en active Application Filing
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- 2003-12-24 EP EP03767317A patent/EP1585745A4/en not_active Withdrawn
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2008
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Patent Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3869553A (en) * | 1972-11-07 | 1975-03-04 | Pfizer | Substituted benzoic acid hypolipemic agents |
BE854857A (en) * | 1976-05-21 | 1977-11-21 | Serdex Soc D Etudes De Rech S | NEW ACETOPHENONE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS |
EP0211670B1 (en) * | 1985-08-09 | 1990-05-09 | Eli Lilly And Company | Di-t-butylphenol compounds |
DE3532280A1 (en) * | 1985-09-11 | 1987-03-12 | Bayer Ag | Sulphur-containing substituted carbonyl compounds |
EP0434394B1 (en) * | 1989-12-21 | 1998-08-05 | Eli Lilly And Company | Compounds for treating inflammatory bowel disease |
EP0621255B1 (en) * | 1993-04-20 | 1997-08-20 | Adir Et Compagnie | Substituted phenoxy-isobutyric acids and esters |
WO1995002406A2 (en) * | 1993-07-15 | 1995-01-26 | Warner-Lambert Company | Use of benzothiophenes and benzofurans for the treatment of inflammatory bowel disease and inflammation assay method |
WO1995015323A1 (en) * | 1993-12-03 | 1995-06-08 | Warner-Lambert Company | IMPROVED PROCESS FOR THE SYNTHESIS OF 3-CHLOROBENZO[b]THIOPHENE-2-CARBONYL CHLORIDES |
EP0722729A2 (en) * | 1995-01-23 | 1996-07-24 | Eli Lilly And Company | Aryl-substituted rhodanines for treating multiple sclerosis |
EP0920862A1 (en) * | 1997-11-14 | 1999-06-09 | Eli Lilly And Company | 2-Arylbenzo b thiophenes useful for the treatment of estrogen deprivation syndrome |
WO2000015214A1 (en) * | 1998-09-11 | 2000-03-23 | Ilexus Pty Limited | Fc RECEPTOR MODULATORS AND USES THEREOF |
WO2001025193A1 (en) * | 1999-10-04 | 2001-04-12 | Nippon Soda Co., Ltd. | Phenolic compounds and recording materials containing the same |
WO2002042289A2 (en) * | 2000-11-27 | 2002-05-30 | Eli Lilly And Company | Process for preparing 3-aryl-benzo[b]thiophenes |
JP2003055340A (en) * | 2001-08-10 | 2003-02-26 | Daikin Ind Ltd | alpha,alpha-DIFLUOROSULFIDE COMPOUND, alpha,alpha-DIFLUOROSULFOXIDE COMPOUND AND alpha,alpha-DIFLUOROSULFONE COMPOUND |
JP2003252794A (en) * | 2002-03-01 | 2003-09-10 | Ono Pharmaceut Co Ltd | Apoptosis inhibitor containing aldose reductase inhibitor as active ingredient |
Non-Patent Citations (5)
Title |
---|
"Aldrich catalogue hadbook of fine chemicals 1996-1997", 1997, ALDRICH CHEMICAL CO. INC., CASTLE HILL NSW 2154, AUSTRALIA, pages: 384, XP008097329 * |
DATABASE WPI Week 200345, Derwent World Patents Index; Class B05, AN 2003-473339, XP008096270 * |
DATABASE WPI Week 200377, Derwent World Patents Index; Class B03, AN 2003-821289, XP008096269 * |
HOGARTH: "Fc receptors are major mediators of antibody based inflammation in autoimmunity", CURRENT OPINION IN IMMUNOLOGY, vol. 14, no. 6, December 2002 (2002-12-01), pages 798 - 802, XP004390321 * |
See also references of EP1585745A4 * |
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WO2005075512A1 (en) * | 2004-02-10 | 2005-08-18 | The Austin Research Institute | Crystal structures and models for fc receptors and uses thereof in the design or identification of fc receptor modulator compounds |
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US9447145B2 (en) | 2004-03-10 | 2016-09-20 | Trinity Therapeutics, Inc. | Compositions for inhibiting immune complex formation in a subject |
US7312361B2 (en) * | 2005-02-08 | 2007-12-25 | The Scripps Research Institute | Inhibitors of transthyretin amyloid fibril formation |
WO2006133486A1 (en) * | 2005-06-14 | 2006-12-21 | The Macfarlane Burnet Institute For Medical Research And Public Health Limited | CRYSTAL STRUCTURES AND MODELS FOR Fc RECEPTOR:Fc COMPLEXES AND USES THEREOF |
US8318785B2 (en) | 2005-07-18 | 2012-11-27 | Orion Corporation | Pharmaceutical compounds |
US8309596B2 (en) | 2007-06-28 | 2012-11-13 | Novartis Ag | Kallikrein 7 modulators |
US8236838B2 (en) | 2008-04-21 | 2012-08-07 | Institute For Oneworld Health | Compounds, compositions and methods comprising isoxazole derivatives |
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US8765409B2 (en) | 2008-05-20 | 2014-07-01 | Merck Sharp & Dohme Corp. | Efficient production of heterologous proteins using mannosyl transferase inhibitors |
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US8343976B2 (en) | 2009-04-20 | 2013-01-01 | Institute For Oneworld Health | Compounds, compositions and methods comprising pyrazole derivatives |
US8410176B2 (en) | 2009-12-29 | 2013-04-02 | Mapi Pharma Ltd. | Intermediate compounds and processes for the preparation of tapentadol and related compounds |
US11747335B2 (en) | 2012-05-25 | 2023-09-05 | University Of Vermont And State Agriculture College | Compositions and methods for assaying platelet reactivity and treatment selection |
EP3704126A4 (en) * | 2017-11-03 | 2020-12-09 | Université de Montréal | Compounds and use thereof in the expansion of stem cells and/or progenitor cells |
US11696928B2 (en) | 2017-11-03 | 2023-07-11 | Universite De Montreal | Compounds and use thereof in the expansion of stem cells and/or progenitor cells |
WO2023014354A1 (en) * | 2021-08-04 | 2023-02-09 | The University Of Vermont And State Agriculture College | Methods for selecting an intracranial atherosclerotic disease patient for treatment |
Also Published As
Publication number | Publication date |
---|---|
US7910770B2 (en) | 2011-03-22 |
US7332631B2 (en) | 2008-02-19 |
US20060264484A1 (en) | 2006-11-23 |
AU2002953533A0 (en) | 2003-01-16 |
AU2010249262B2 (en) | 2011-11-10 |
US20110144170A1 (en) | 2011-06-16 |
JP2006516133A (en) | 2006-06-22 |
CA2511356A1 (en) | 2004-07-15 |
AU2010249262A1 (en) | 2011-01-06 |
US20080146632A1 (en) | 2008-06-19 |
EP1585745A1 (en) | 2005-10-19 |
EP1585745A4 (en) | 2008-07-09 |
AU2003291859A1 (en) | 2004-07-22 |
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