WO2004048378A1 - Pyrazoloquinolines with immunomodulating activity - Google Patents
Pyrazoloquinolines with immunomodulating activity Download PDFInfo
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- WO2004048378A1 WO2004048378A1 PCT/SE2003/001805 SE0301805W WO2004048378A1 WO 2004048378 A1 WO2004048378 A1 WO 2004048378A1 SE 0301805 W SE0301805 W SE 0301805W WO 2004048378 A1 WO2004048378 A1 WO 2004048378A1
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- 0 O=*(c1cc(N2N=C3c(cccc4F)c4NC=C3C2=O)ccc1)Cl Chemical compound O=*(c1cc(N2N=C3c(cccc4F)c4NC=C3C2=O)ccc1)Cl 0.000 description 1
- USQKIMDPWYHGHB-UHFFFAOYSA-N O=C(c(cc1)ccc1N1N=C2c(cccc3F)c3SC=C2C1=O)NCCCCN1CCCC1 Chemical compound O=C(c(cc1)ccc1N1N=C2c(cccc3F)c3SC=C2C1=O)NCCCCN1CCCC1 USQKIMDPWYHGHB-UHFFFAOYSA-N 0.000 description 1
- GJAATEGEGYTUJI-UHFFFAOYSA-N OC(c(cc1)ccc1N1N=C2c(cccc3)c3NC(C3CC3)=C2C1=O)=O Chemical compound OC(c(cc1)ccc1N1N=C2c(cccc3)c3NC(C3CC3)=C2C1=O)=O GJAATEGEGYTUJI-UHFFFAOYSA-N 0.000 description 1
- IZGRGHVLSZXBEZ-UHFFFAOYSA-N OC(c(cc1)ccc1N1N=C2c(cccc3F)c3SC=C2C1=O)=O Chemical compound OC(c(cc1)ccc1N1N=C2c(cccc3F)c3SC=C2C1=O)=O IZGRGHVLSZXBEZ-UHFFFAOYSA-N 0.000 description 1
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to novel heterocyclic compounds, to methods for their preparation, to compositions containing them, and to methods and use for clinical treatment of medical conditions which may benefit from immunomodulation, including rheumatoid arthritis, multiple sclerosis, diabetes, asthma, transplantation, systemic lupus erythematosis and psoriasis. More particularly the present invention relates to novel heterocyclic compounds, which are CD80 antagonists capable of inhibiting the interactions between CD80 and CD28. Background of the invention
- the immune system possesses the ability to control the homeostasis between the activation and inactivation of lymphocytes through various regulatory mechanisms du- ring and after an immune response. Among these are mechanisms that specifically inhibit and/or turn off an immune response.
- an antigen is presented by MHC molecules to the T-cell receptor, the T-cells become properly activated only in the presence of additional co-stimula- tory signals.
- accessory signals there is no lymphocyte activation and either a state of functional inactivation termed anergy or tolerance is induced, or the T-cell is specifically deleted by apoptosis.
- Ri and R 3 independently represent H; F; Cl ; Br; -N0 2 ; -CN; C ⁇ -C 6 alkyl optionally substituted by F or Cl ; or Ci- C s alkoxy optionally substituted by F;
- R 2 represents H, or optionally substituted C ⁇ -C 6 alkyl, C 3 -C 7 cycloalkyl or optionally substituted phenyl;
- Y represents -0-, -S-, N-oxide, or -N(R 5 )- wherein R 5 represents H or C ⁇ -C 6 alkyl;
- X represents a bond or a divalent C ⁇ -C 3 alkylene radical
- R e represents H, or a radical of formula -(Alk) b -Q wherein b is 0 or 1, and Alk is an optionally substituted divalent straight chain or branched C1-C12 alkylene, C 2 -C ⁇ 2 alkenylene or C 2 - C 12 alkynylene radical which may be interrupted by one or more non-adjacent -0-, -S- or -N(R 8 )- radicals wherein R 8 represents H or C 1 -C4 alkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl, or C 3 -C 6 cycloalkyl, and
- Q represents H; -CF 3 ; -OH; -SH; -NR 8 R 8 wherein each R 8 may be the same or different; an ester group; or an optionally substituted phenyl, C 3 -C cycloalkyl, C 5 -C 7 cycloalkenyl or heterocyclic ring having from 5 to 8 ring atoms; and
- R 7 represents H or C ⁇ -C 6 alkyl; or when taken together with the atom or atoms to which they are attached Re and R 7 form an optionally substituted heterocyclic ring having from 5 to 8 ring atoms.
- CD80 antagonists are CD80 antagonists. They inhibit the interaction between CD80 and CD28 and thus the activation of T cells, thereby modulating the immune response. Accordingly the invention also includes:
- a method of immunomodulation in humans and non-human primates comprising administration to a subject in need of such treatment an immunomodulatory effective dose of a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof, (iv) a pharmaceutical or veterinary composition com- prising a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof together with a pharmaceutically or veterinarily acceptable excipient or carrier.
- Conditions which benefit from immunomodulation include: Adrenal insufficiency
- alkylene refers to a straight or branched alkyl chain having two unsatisfied valencies, for example -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -,
- heteroaryl refers to a 5- or 6- membered aromatic ring containing one or more he- teroatoms.
- Illustrative of such groups are thienyl, fu- ryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl , triazolyl, thia- diazolyl, oxadiazolyl , pyridinyl, pyridazinyl, pyri i- dinyl , pyrazinyl, triazinyl .
- heterocyclyl or “heterocyclic” includes “heteroaryl” as defined above, and in particular means a 5-8 membered aromatic or non- aromatic heterocyclic ring containing one or more hetero- atoms selected from S, N and O, including for example, pyrrolyl, furanyl , thienyl, piperidinyl , imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl , pyra- zolyl, pyridinyl, pyrrolidinyl , pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzofuranyl , pyranyl , isoxazolyl, quinuclidinyl, aza-bicyclo [3.2.1] octanyl , benzimidazolyl , methylenedioxypheny
- substituted as applied to any moiety herein means substituted with one or more of the following substituents, namely (C ⁇ -C 6 ) alkyl , trifluoromethyl, (C ⁇ -C 6 ) alkoxy (including the special case where a ring is substituted on adjacent ring C atoms by methylenedioxy or ethylenedioxy) , trifluoromethoxy, (C ⁇ -C 6 ) alkylthio, phenyl, benzyl, phenoxy, (C 3 -C 8 ) cycloalkyl , hydroxy, mercap- to, amino, fluoro, chloro, bromo, cyano, nitro, oxo, -COOH, -S0 2 OH, -CONH 2 , -S0 2 NH 2 , -C0R A , -COOR A , -S0 2 OR A , -NHC
- R A and R B are independently a (C ⁇ -C 6 ) alkyl group.
- substituted means substituted by (C 3 -C 8 ) cycloalkyl , phenyl, benzyl or phenoxy
- the ring thereof may itself be substituted with any of the foregoing, except (C 3 -C 8 ) cycloalkyl phenyl, benzyl or phenoxy.
- carbocyclyl or “carbocyclic” refers to a 5-8 membered ring whose ring atoms are all carbon.
- Some compounds of the invention contain one or more chiral centres because of the presence of asymmetric carbon atoms .
- the presence of asymmetric carbon atoms gives rise to stereoisomers or diastereoisomers with R or S stereochemistry at each chiral centre.
- the invention includes all such stereoisomers and diastereoisomers and mixtures thereof .
- Salts of salt forming compounds of the invention include physiologically acceptable acid addition salts for example hydrochlorides, hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates; and base addition salts, for example sodium, potassium, magnesium, and calcium salts.
- physiologically acceptable acid addition salts for example hydrochlorides, hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates
- base addition salts for example sodium, potassium, magnesium, and calcium salts.
- quaternary amino salts are also feasable, and are included in the invention.
- the compounds of the invention the following are examples of the several structural variables:
- Ri may be, for example, H, F, Cl , methyl, methoxy, or methylenedioxy. Currently it is preferred that Ri is H, Cl or especially F; R 2 may be, for example H, methyl, methoxy, cyclopropyl, phenyl, or fluoro-, chloro-, methyl, or methoxy- substituted phenyl. H or cyclopropyl is presently preferred;
- R 3 may be, for example, H, F, Cl, methyl, methoxy, or methylenedioxy. Currently it is preferred that R 3 is F or Cl , and it is most preferred that R 3 be H;
- Y may be, for example, -0-, -S-, or -N(R 5 )- wherein R 5 represents H or methyl.
- -NH- or -S- is presently preferred.
- X may be, for example a bond, or a -CH 2 - or -CH 2 CH 2 - radical . A bond is presently preferred.
- R 7 is preferably H, but a wide range of R 6 substituents have given rise to highly active compounds of the invention. Many exemplary R 6 substituents appear in the compounds of the Examples below.
- R s may be, for example, H or a radical of formula -Alk b -Q wherein b is 0 or 1 and
- Alk may be, for example a -(CH 2 ) n -, -CH((CH 2 ) ra CH 3 ) (CH a ) n -, -C ( (CH 2 ) m CH 3 ) ((CH 2 ) P CH 3 ) (CH 2 ) n -, - (CH 2 ) n -O- (CH 2 ) m - , - (CH 2 ) n -NH- (CH 2 ) m - , or
- Q may represent H, -OH, -COOCH 3 , phenyl, cyclopropyl, cyclopentyl, cyclohexyl, pyridyl, furyl, thienyl, or oxazolyl ;
- R 7 may be, for example, H, or when taken together with the atom or atoms to which they are attached R e and R 7 may form a heterocyclic ring of 5, 6 or 7 members.
- R 4 groups include those present in the compounds of the Examples herein.
- compounds of the invention may be prepared by synthetic methods known in the literature, from compounds which are commercially available or are accessible from commercially available compounds.
- Tin (II) chloride dihydrate (12.5 g, 0.055 mol) was added in one portion to a stirred solution of 2- (4-nitro- phenyl) -6-fluoro-2 , 5-dihydro-pyrazolo [4 , 3-c] quinolin-3- one (intermediate 1) (3.59 g, 0.011 mol) in ethyl alcohol (110 ml) at room temperature. The mixture was then heated to 80 °C for 8 h, cooled to room temperature and filtered to leave a yellow solid.
- 3-Hydrazinobenzoic acid (1.91 g, 0.013 mol) was added in one portion to a stirred solution of 4-chloro-8- fluoro-quinoline-3-carboxylic acid ethyl ester (2.93 g, 0.011 mol) in n-butanol (60 ml) at room temperature.
- the solution was heated to reflux for 16 h, cooled to room temperature and the resulting yellow solid filtered, washed with tert-butyl methyl ether and then dried.
- the solid was redissolved in a solution of tetrahydrofuran : water (2:1; 21 ml) and lithium hydroxide (1.27 g, 0.031 mol) was then added.
- 3-Methoxypropylamine (0.026g, 0.29mmol) was added to a stirred solution of 3- (6-fluoro-3 -oxo-3 , 5-dihydropyrazolo [4 , 3-c] quinolin-2-yl) -benzoyl chloride (intermediate 4) (26 mg 0.29mmol) in tetrahydrofuran (2 ml) and the mixture stirred at room temperature for 15 min. Triethylamine (0.2 ml, 1.4 mmol) was then added and the resulting mixture stirred overnight.
- Examples 53 to 64 were prepared by the method of 15 example 50, using the appropriate amine.
- reaction mixture 125°C for 2h; 15 ml of solvent was then distilled.
- sodium ethoxide (2 M, 15 ml) in ethanol reaction mixture turns red
- This red mixture was stirred at 120°C for 2 h; 15 ml of solvent was again distilled.
- the reaction mixture was left to cool to room temperature, diluted with ethyl acetate (1 litre), extracted with HCl 0.1 M and water.
- Step 2 4 -Chloro-2-cyclopropyl-quinoline- 3 -carboxylic acid ethyl ester
- Phosphorus oxychloride (0.77 ml, 0.082 mols) was added in one portion to a suspension of 2 -cyclopropyl -4 -ox ⁇ -1, 4- dihydro-quinoline-3-carboxylic acid ethyl ester (1.0 g, 0.041 mols) in acetonitrile and the mixture was heated at 75°C for 90 minutes (becomes a clear solution above 65°C) .
- Step 5 N- (3 -Dimethylamino propyl) -4- (4-cyclopropyl-3-oxo-3 , 5- dihydro-pyrazolo [4, 3-c] quinolin-2-yl] -benzamide
- 2-Fluorothiophenol (5.0 g, 39 mmol) was dissolved in tetrahydrofuran (50 ml) under a nitrogen atmosphere. Triethylamine (3.94 g, 5.33 ml, 85.8 mmol) was added. Acrylic acid (2.81 g, 2.67 ml, 39 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction solution over 2 h at room temperature. The mixture was stirred at room temperature overnight. IM Hydrochloric acid (50 ml) was added and the phases were separated. The aqueous phase was washed with ethyl acetate (2 x 50 ml) .
- Methyl cyanoformate (0.935 g, 0.87 ml) was dissolved in tetrahydrofuran (2 ml) and added dropwise to the reaction solution. Stirring was continued at low temperature for 1 h, the mixture was then allowed to warm to room temperature. Saturated ammonium chloride solution (20 ml) and water (10 ml) were added, the phases mixed for 5 min and separated. The aqueous phase was washed with ethyl acetate (2 x 100 ml) and the combined organic phases were dried over magnesium sulphate. The mixture was filtered and the solvent removed under vacuum to give an orange oil.
- the crude oil was purified by column chromatography; mobile phase: hexanes, gradient to hexanes / ethyl acetate [90:10].
- the title compound was isolated as a yellow solid (1.19 g, 4.95 mmol, 45%).
- Methyl 8-fluoro-4-oxothiochromane-3 -carboxylate (1.19 g, 4.95 mmol) and 4-hydrazinobenzoic acid (755 mg, 4.95 mmol) were mixed with glacial acetic acid (10 ml) . The mixture was heated to reflux for 4 h. Excess acetic acid was removed under vacuum to give an orange oil . Ethyl acetate (10 ml) was added and the mixture sonicated. Precipitation of an orange solid was observed. The solids were collected by filtration and washed with ethyl acetate. The filter cake was taken up in dimethyl suphoxide (10 ml) and air-oxidised at room temperature for one week.
- europium and allophycocyanin are associated with CD28 and CD80 indirectly (through antibody linkers) to form a complex, which brings the europium and APC into close proximity to generate a signal.
- the complex comprises the following six proteins: fluorescent label 1, linker antibody 1, CD28 fusion protein, CD80 fusion protein, linker antibody 2, and fluorescent label 2. The table below describes these reagents in greater detail .
- Non-specific interaction was measured by substituting a mouse Fab fragment (C215) for the CD80 mouse Fab fragment fusion protein (1.9 ⁇ g/ml) .
- the assay was carried out in black 384 well plates in a final volume of 30 ⁇ l.
- Assay buffer 50mM Tris-HCl, 150mM NaCl pH7.8, containing 0.1% BSA (w/v) added just prior to use.
- the EC 50 results for the compounds of Examples 15, 21, 29, 35 and 83 were 8 ⁇ M, 1.9 ⁇ M, 950 nM, 148nM and 90nM respectively.
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Abstract
Description
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Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE60311861T DE60311861T2 (en) | 2002-11-22 | 2003-11-21 | PYRAZOLOCHINOLINE WITH IMMUNOMODULATING EFFECT |
NZ540081A NZ540081A (en) | 2002-11-22 | 2003-11-21 | Pyrazoloquinolines with immunomodulating activity |
CA002506524A CA2506524A1 (en) | 2002-11-22 | 2003-11-21 | Pyrazoloquinolines with immunomodulating activity |
EP03773026A EP1562944B1 (en) | 2002-11-22 | 2003-11-21 | Pyrazoloquinolines with immunomodulating activity |
JP2005510306A JP2006509047A (en) | 2002-11-22 | 2003-11-21 | Pyrazoloquinolines with immunomodulatory activity |
RU2005119639/04A RU2328496C2 (en) | 2002-11-22 | 2003-11-21 | Pyrazolquinolines with immunomodulating activity |
CNB2003801066699A CN100347173C (en) | 2002-11-22 | 2003-11-21 | Pyrazoloquinolines with immunomodulating activity |
AU2003279687A AU2003279687A1 (en) | 2002-11-22 | 2003-11-21 | Pyrazoloquinolines with immunomodulating activity |
NO20053018A NO20053018L (en) | 2002-11-22 | 2005-06-20 | Pyrazoloquinolines with immunomodulatory activity. |
HK06106518A HK1086562A1 (en) | 2002-11-22 | 2006-06-07 | Pyrazoloquinolines with immunomodulating activity |
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US42824002P | 2002-11-22 | 2002-11-22 | |
SE0203471-8 | 2002-11-22 | ||
US60/428240 | 2002-11-22 | ||
SE0203471A SE0203471D0 (en) | 2002-11-22 | 2002-11-22 | Immunomodulatory compunds |
SE0301299A SE0301299D0 (en) | 2003-05-06 | 2003-05-06 | Immunomodulatory compounds |
SE0301299-4 | 2003-05-06 | ||
US48212203P | 2003-06-25 | 2003-06-25 | |
US60/482122 | 2003-06-25 | ||
SE0301851-2 | 2003-06-25 | ||
SE0301851A SE0301851D0 (en) | 2003-06-25 | 2003-06-25 | Immunomodulatory compounds |
Publications (1)
Publication Number | Publication Date |
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WO2004048378A1 true WO2004048378A1 (en) | 2004-06-10 |
Family
ID=32398347
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE2003/001805 WO2004048378A1 (en) | 2002-11-22 | 2003-11-21 | Pyrazoloquinolines with immunomodulating activity |
Country Status (14)
Country | Link |
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US (2) | US7081456B2 (en) |
EP (2) | EP1813616B1 (en) |
JP (1) | JP2006509047A (en) |
CN (1) | CN100347173C (en) |
AT (1) | ATE353898T1 (en) |
AU (1) | AU2003279687A1 (en) |
CA (1) | CA2506524A1 (en) |
DE (1) | DE60311861T2 (en) |
ES (1) | ES2282693T3 (en) |
HK (1) | HK1086562A1 (en) |
NO (1) | NO20053018L (en) |
NZ (1) | NZ540081A (en) |
RU (1) | RU2328496C2 (en) |
WO (1) | WO2004048378A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008043072A2 (en) * | 2006-10-05 | 2008-04-10 | Biogen Idec Inc. | Cd80 antagonists for treating neoplastic disorders |
US7816361B2 (en) | 2003-11-04 | 2010-10-19 | Medigene Limited | Immuno inhibitory pyrazolone compounds |
US7932253B2 (en) | 2004-08-09 | 2011-04-26 | Medigene Ag | Immunomodulating oxopyrrazolocinnolines as CD80 inhibitors |
US8309552B2 (en) | 2003-03-14 | 2012-11-13 | Medigene Ag | Immunomodulating heterocyclic compounds |
EP2676666A1 (en) * | 2012-06-20 | 2013-12-25 | Eidgenössische Technische Hochschule Zürich (ETH) | Compounds for use in diagnosis or therapy of vulnerable atherosclerotic plaques |
EP2883883A1 (en) | 2013-12-16 | 2015-06-17 | Cardio3 Biosciences S.A. | Therapeutic targets and agents useful in treating ischemia reperfusion injury |
US9809589B2 (en) | 2012-12-22 | 2017-11-07 | Kbp Biosciences Co., Ltd. | Crystal form of compound used as mineralocorticoid receptor antagonist and preparation method therefor |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE60326639D1 (en) * | 2002-12-16 | 2009-04-23 | Active Biotech Ab | Tetracyclic immunomodulatory compounds |
CN102977095B (en) * | 2012-12-03 | 2015-10-28 | 华东理工大学 | Pyrazolo quinolines and uses thereof |
CN110698456B (en) * | 2019-11-06 | 2021-05-14 | 重庆医药高等专科学校 | Synthesis method of 2, 3-dihydrothiochromen-4-one and derivatives thereof |
Citations (3)
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WO1991011448A1 (en) * | 1990-02-02 | 1991-08-08 | The Boots Company Plc | Therapeutic agents |
WO1997034893A1 (en) * | 1996-03-20 | 1997-09-25 | Astra Pharmaceuticals Ltd. | Pharmaceutically useful compounds |
WO2003004495A1 (en) * | 2001-07-04 | 2003-01-16 | Active Biotech Ab | Novel immunomodulating compounds |
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US4268516A (en) * | 1978-10-11 | 1981-05-19 | Pfizer Inc. | [1]Benzothiopyrano[4,3-c]pyrazoles as immunoregulatory agents |
US4312870A (en) * | 1979-06-21 | 1982-01-26 | Ciba-Geigy Corporation | Pyrazoloquinolines |
PH21213A (en) * | 1984-10-26 | 1987-08-21 | Fujisawa Pharmaceutical Co | Benzene- and pyrazole- fused heterocyclic compound and pharmaceutical composition comprising the same |
US4758427A (en) * | 1985-08-08 | 1988-07-19 | Ciba-Geigy Corporation | Enhanced absorption of psychoactive 2-aryl-pyrazolo quinolines as a solid molecular dispersion in polyvinylpyrrolidone |
GB9002423D0 (en) * | 1990-02-06 | 1990-04-04 | Boots Co Plc | Therapeutic agents |
CN1069272A (en) * | 1991-08-02 | 1993-02-24 | 布茨公司 | The method for preparing benzo pyrrole or thiapyran and pyrazoles |
US6642249B2 (en) * | 2001-07-04 | 2003-11-04 | Active Biotech Ab | Immunomodulating compounds |
-
2003
- 2003-11-21 AT AT03773026T patent/ATE353898T1/en not_active IP Right Cessation
- 2003-11-21 US US10/717,519 patent/US7081456B2/en not_active Expired - Lifetime
- 2003-11-21 EP EP07102257A patent/EP1813616B1/en not_active Expired - Lifetime
- 2003-11-21 RU RU2005119639/04A patent/RU2328496C2/en not_active IP Right Cessation
- 2003-11-21 NZ NZ540081A patent/NZ540081A/en unknown
- 2003-11-21 AU AU2003279687A patent/AU2003279687A1/en not_active Abandoned
- 2003-11-21 EP EP03773026A patent/EP1562944B1/en not_active Expired - Lifetime
- 2003-11-21 CA CA002506524A patent/CA2506524A1/en not_active Abandoned
- 2003-11-21 JP JP2005510306A patent/JP2006509047A/en not_active Withdrawn
- 2003-11-21 WO PCT/SE2003/001805 patent/WO2004048378A1/en active IP Right Grant
- 2003-11-21 ES ES03773026T patent/ES2282693T3/en not_active Expired - Lifetime
- 2003-11-21 CN CNB2003801066699A patent/CN100347173C/en not_active Expired - Fee Related
- 2003-11-21 DE DE60311861T patent/DE60311861T2/en not_active Expired - Lifetime
-
2005
- 2005-06-20 NO NO20053018A patent/NO20053018L/en not_active Application Discontinuation
-
2006
- 2006-05-30 US US11/442,548 patent/US7291612B2/en not_active Expired - Lifetime
- 2006-06-07 HK HK06106518A patent/HK1086562A1/en not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991011448A1 (en) * | 1990-02-02 | 1991-08-08 | The Boots Company Plc | Therapeutic agents |
WO1997034893A1 (en) * | 1996-03-20 | 1997-09-25 | Astra Pharmaceuticals Ltd. | Pharmaceutically useful compounds |
WO2003004495A1 (en) * | 2001-07-04 | 2003-01-16 | Active Biotech Ab | Novel immunomodulating compounds |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8309552B2 (en) | 2003-03-14 | 2012-11-13 | Medigene Ag | Immunomodulating heterocyclic compounds |
US7816361B2 (en) | 2003-11-04 | 2010-10-19 | Medigene Limited | Immuno inhibitory pyrazolone compounds |
US8163757B2 (en) | 2003-11-04 | 2012-04-24 | Medigene Ag | Immuno inhibitory pyrazolone compounds |
US7932253B2 (en) | 2004-08-09 | 2011-04-26 | Medigene Ag | Immunomodulating oxopyrrazolocinnolines as CD80 inhibitors |
WO2008043072A2 (en) * | 2006-10-05 | 2008-04-10 | Biogen Idec Inc. | Cd80 antagonists for treating neoplastic disorders |
WO2008043072A3 (en) * | 2006-10-05 | 2008-12-18 | Biogen Idec Inc | Cd80 antagonists for treating neoplastic disorders |
EP2676666A1 (en) * | 2012-06-20 | 2013-12-25 | Eidgenössische Technische Hochschule Zürich (ETH) | Compounds for use in diagnosis or therapy of vulnerable atherosclerotic plaques |
US9809589B2 (en) | 2012-12-22 | 2017-11-07 | Kbp Biosciences Co., Ltd. | Crystal form of compound used as mineralocorticoid receptor antagonist and preparation method therefor |
EP2883883A1 (en) | 2013-12-16 | 2015-06-17 | Cardio3 Biosciences S.A. | Therapeutic targets and agents useful in treating ischemia reperfusion injury |
Also Published As
Publication number | Publication date |
---|---|
CN1729191A (en) | 2006-02-01 |
CA2506524A1 (en) | 2004-06-10 |
RU2328496C2 (en) | 2008-07-10 |
JP2006509047A (en) | 2006-03-16 |
EP1813616A3 (en) | 2007-08-08 |
US20060217411A1 (en) | 2006-09-28 |
US20040116461A1 (en) | 2004-06-17 |
ATE353898T1 (en) | 2007-03-15 |
RU2005119639A (en) | 2006-01-20 |
NO20053018L (en) | 2005-08-22 |
AU2003279687A1 (en) | 2004-06-18 |
US7291612B2 (en) | 2007-11-06 |
EP1813616A2 (en) | 2007-08-01 |
EP1562944B1 (en) | 2007-02-14 |
DE60311861T2 (en) | 2007-11-22 |
DE60311861D1 (en) | 2007-03-29 |
CN100347173C (en) | 2007-11-07 |
US20050203118A9 (en) | 2005-09-15 |
ES2282693T3 (en) | 2007-10-16 |
NZ540081A (en) | 2008-03-28 |
NO20053018D0 (en) | 2005-06-20 |
HK1086562A1 (en) | 2006-09-22 |
EP1813616B1 (en) | 2013-03-27 |
US7081456B2 (en) | 2006-07-25 |
EP1562944A1 (en) | 2005-08-17 |
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