WO2008037476A1 - Oxadiazole derivatives with anti-inflammatory and immunosuppressive properties - Google Patents
Oxadiazole derivatives with anti-inflammatory and immunosuppressive properties Download PDFInfo
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- WO2008037476A1 WO2008037476A1 PCT/EP2007/008431 EP2007008431W WO2008037476A1 WO 2008037476 A1 WO2008037476 A1 WO 2008037476A1 EP 2007008431 W EP2007008431 W EP 2007008431W WO 2008037476 A1 WO2008037476 A1 WO 2008037476A1
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- 0 *c1cccnc1O Chemical compound *c1cccnc1O 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Definitions
- the present invention relates to polycyclic compounds, processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
- R 1 is a residue of formula (a)
- R 5 and R 6 form together with the 2 carbon atoms to which they are attached another ring, for example a residue of formula (b),
- Z is CH or N, preferably CH; each of R b and R' b , independently, is C ⁇ alkyl; provided that at most one of R 5 and R 6 is H; R 2 is -R 7 -NR 8 Rg wherein R 7 is optionally substituted C 1-4 alkylene; wherein two
- R 8 and R 9 independently, is H, optionally substituted C 1-8 alkyl, R d -CO or a heterocyclic group, or R 8 and R 9 form together with the nitrogen atom to which they are bound an optionally substituted heterocyclic group; and R d is C 1-4 alkyl; or R 2 is an optionally substituted heterocyclic group; and c ⁇ u i ui r ⁇ 3 di iu I ⁇ 4 is ⁇ , provided that
- R 1 is other than 2-CF 3 -4-biphenylyl, 3-CF 3 -4-trifluoroethoxy- phenyl or 3-CF 3 -4-isopropoxy-phenyl;
- R 2 is -C(CH 3 ) 2 -NH 2
- Ri is other than 2-CF 3 -4-biphenylyl
- R 1 is substituted biphenylyl, 4-phenoxy-phenyl or 4-(phenyl-C 1 . 4 alkoxy)-phenyl wherein at least one of the phenyl groups is monosubstituted; or phenyl substituted by one or more substituents selected from halogen, nitrile, C 1-8 alkyl, haloC 1-8 alkyl, C 1-8 alkoxy, halod.
- the typical points of attachment in a residue of formula (a) are any of the positions being not occupied by a substituent R 5 or R 6 .
- the substituents R 5 and R 6 are meta and para in relation to the oxadiazol ring.
- the typical points of attachment in a residue of formula (b) are any of the free positions in the ring carrying the group Z.
- HaIo or halogen may be fluorine, chlorine or bromine, preferably fluorine or chlorine.
- Alkyl or alkoxy as a group or present in a group may be straight or branched.
- C 1-4 alkylene may be straight or branched.
- Halo-alkyl or halo-alkoxy as a group or a moiety present in a group may be the corresponding alkyl or alkoxy group substituted by 1 to 5 halogen, e.g. CF 3 or CF 3 -CH 2 -O-.
- Heterocyclic group may be a 5 or 6 membered saturated heterocyclic ring comprising 1 or 2 heteroatoms selected from N, S and O, and optionally substituted. Suitable examples include e.g. pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl or morpholino.
- the heterocyclic ring When the heterocyclic ring is substituted, it may be a substituent on a cyclic carbon or nitrogen atom.
- Examples of a substituent on a cyclic carbon may be e.g. OH, C ⁇ alkyl or hydroxy- C 1-4 alkylene.
- Examples of a substituent on a nitrogen atom may be C 1-4 alkyl.
- R 7 is optionally substituted C 1-6 alkylene
- the alkylene may be substituted by OH, C 1 . 4 alkoxy, hydroxy-C 1-4 alkylene and/or d ⁇ alkoxy-C ⁇ alkylene.
- R 8 or R 9 is optionally substituted C 1-6 alkyl
- the substitutent may be OH or C 1-4 alkoxy; preferably the substituent is on the terminal carbon atom of the alkyl chain.
- R 8 and R 9 form together with the nitrogen atom to which they are bound a heterocyclic group, it may be a heterocyclic ring as defined above, except that the heterocyclic residue formed by R 8 and R 9 is attached by a nitrogen atom.
- R 1 is substituted biphenylyl, 4-phenoxy-phenyl or 4-(phenyl-C 1-4 alkoxy)-phenyl
- either one and/or both phenyl moieties may be substituted, e.g. mono- or di-substituted e.g. by halogen, C 1-8 alkyl, C ⁇ alkoxy, haloCi -8 alkyl, haloC ⁇ alkoxy or nitrile.
- at least one phenyl moiety of the biphenylyl, 4-phenoxy-phenyl or 4-(phenyl-C 1 ⁇ alkoxy)-phenyl is monosubstituted, e.g. as indicated above.
- each phenyl moiety of the biphenylyl, 4-phenoxy-phenyl or 4-(phenyl-C 1-4 alkoxy)-phenyl is monosubstituted, e.g. as indicated above, e.g. by haloC 1-8 alkyl, and optionally as substitutent on the second phenyl moiety either halogen, C 1-8 alkyl or C ⁇ alkoxy, haloCi -8 alkyl or haloC 1-8 alkoxy.
- R 1 When R 1 is substituted phenyl, it may be mono- or di-substituted. When R 1 is disubstituted phenyl, one substituent may preferably be haloC 1-8 alkyl or haloC 1-8 alkoxy and the second substitutent as indicated above.
- R 1 is a residue of formula (a); - A -
- R 2 is -R 7 -NR 8 R 9 or a heterocyclic ring attached by a carbon atom, wherein the variables have the meanings provided hereinbefore;
- R 3 is H
- R 5 srsd ° 6 do not form another ring and are independeriiiy S ⁇ ieuied from H; ⁇ aiogen; d-salkyl optionally substituted by OH, or C 1-4 alkoxy; halo-Ci -8 alkyl; CN; Ci -8 alkoxy; halo- Ci. 8 alkoxy; and phenyl; provided that at least one of R 5 or R 6 is different from H;
- R 5 and R 6 are other than H
- R 5 and R 6 are not both Ci- 8 alkoxy at the same time;
- R 1 is a residue of formula (a) and R 2 is a heterocyclic ring attached at a carbon atom.
- the compounds of formula I may exist in free form or in salt form, e.g. addition salts with e.g. organic or inorganic acids, for example, hydrochloric acid or acetic acid.
- R 7 may comprise an asymmetric carbon atom when R 7 is branched alkylene or substituted alkylene. It is to be understood that the present invention embraces all enantiomers and conformers and their mixtures. Similar considerations apply in relation to starting materials exhibiting asymmetric carbon atoms as mentioned above.
- the present invention also includes a process for the production of a compound of formula I, which process comprises a) condensing a compound of formula Il wherein R 1 is as defined above, or a functional derivative thereof, with a compound of formula III (route A); or b) converting a compound of formula IV or V to a compound of formula I (route B or C), and and recovering the resulting compound of formula I in free form or in form of a salt, and, where required converting the compound of formula I obtained in free form into the desired salt form or vice versa.
- All reactions may be performed in a solvent e.g. methanol, ethanol, tetrahydrofuran, toluene, dichloromethane, 1 ,2-dichloroethane, N-methylpyrrolidone, xylenes, ethyl acetate, diethyl ether, hexanes, cyclohexanes, dimethylformamide, acetone, dimethylsulfoxide, tert- butylmethyl ether. All compounds may be isolated using methods known to those skilled in the art (e.g. crystallization, silica gel chromatography, HPLC).
- a compound of formula Il may be condensed with a N-hydroxy amidine of formula III in the presence of a coupling agent, e.g. EDC or HOBt, and in the presence or absence of a suitable base (for example a tertiary amine such as Et 3 N or H ⁇ nig's base) in a suitable solvent (for example dioxane, THF, toluene, DMF, acetonitrile).
- a functional derivative of an acid of formula Il may be e.g. an acid chloride or an activated ester.
- the acid of formula Il may be activated prior to the condensation as the corresponding acid chloride or as an activated ester (for example succinimide ester) (see scheme 2).
- Scheme 2 :
- routes B compounds of formulae IV-a,b are converted respectively to compounds of formulae l-a,b by deprotection of either a carboxylic function or an amine function.
- Standard protecting group for carboxylic acid for example esters
- for amine for example carbamate.
- route B a compound of formula a to l-c is obtained by alkylation or acylation of the nitrogen atom of a compound of formula IV-c using methods known by in the art (see scheme 3).
- a compounds of formula V may be converted into a compound of formula I wherein R 6 is C 1-4 alkoxy by either alkylation of a compound of formula V wherein Y is OH, using standard conditions (e.g. using a base such as K 2 CO 3 , CsCO 3 or NaOH and a solvent, e.g. THF, ethanol, acetonitrile, acetone and the appropriate electrophilic alkylating agent) or by displacement of fluoride in a compound of formula V wherein Y is F, using standard conditions (for example using a base such as K 2 CO 3 , CsCO 3 or NaH and a solvent e.g. THF 1 acetonitrile, DMF and the appropriate alcohol) (see scheme 4).
- a base such as K 2 CO 3 , CsCO 3 or NaOH
- a solvent e.g. THF 1 acetonitrile, DMF and the appropriate alcohol
- a compound of formula II, used as starting materials, may be prepared as follows: Compounds of formulae Vl-a,b if not commercially available or described in the literature may be synthesized following 2 routes. Biaryl carboxylic acids of formula Vl-a may be obtained using Pd catalysed Suzuki conditions from 4-chloro benzoic acids and the corresponding aryl boronic acid (see scheme 5).
- the compounds are either known or may be prepared analogously to methods known in the art or as disclosed hereinafter.
- the present invention relates to any aspect of the disclosed and described claims and/or examples individually, collectively or to any selections and/or any combinations thereof.
- Boc 2 O tert.-butyloxycarbonylanhydride
- HOBt hydroxybenzotriazole
- EDCHCI 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride
- R 5 , R 6 , R 2 , R 3 and R 4 are as defined in Table 1 below, are obtained.
- Example 7 3-(2-EthvM-(5-r4-(2.2.2-trifluoro-ethoxv)-3-trifluoromethvl-phenvll- 1 ,2,4]oxadiazol-3-yl ⁇ -benzenesulfonylamino)-propionic acid
- N-Boc-4-aminoethylbenzonitrile 14g; 60mmol
- THF 500ml
- the reaction mixture is then stirred at room temperature for 16 hours.
- the reaction mixture is diluted with water and THF is removed under vacuo.
- the resulting precipitate is collected by filtration and dried. Pure title compound is obtained by recrystallization from diethylether.
- N-Boc-4-aminomethyl-N-hydroxy- benzamidine (266mg; 1 mmol) is added to the reaction mixture and stirred for 30 minutes at room temperature, followed by stirring overnight at 95 0 C.
- R 5 , R 6 , R 2 and R 3 are as defined in Table 2 below, are obtained.
- Example 85 4- ⁇ 5-[4-(2,2,2-Trifluoro-ethoxy)-3-trifluoromethyl-phenyl]-[1 ,2,4]oxadiazol-3-yl ⁇ - 2-trifluoromethoxy-benzenesulfonamide
- R 5 , R 6 , R 2 , R 3 and R 4 are as defined in Table 3 below, are obtained.
- the compounds of formula I in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties , e.g. as S1 P1 receptor agonists, e.g. as indicated in vitro and in vivo tests and are therefore indicated for therapy.
- the compounds of formula I have binding affinity to individual human S1 P receptors as determined in following assays:
- SI P 1 (EDG-1 ) GTP [ ⁇ - 35 S] binding assay Homogenized membranes are prepared from CHO cell clones stably expressing a human EDG-1 N-terminal c-myc tag. Cells are grown in suspension in two 850 cm 2 roller bottles for three or fours days before harvesting. The cells are centrifuged down, washed once with cold PBS, and resuspended in ⁇ 20 ml of Buffer A (20 mM HEPES, pH 7.4, 0 mM EDTA, EDTA-free complete protease inhibitor cocktail [1 tablet/25 ml]).
- Buffer A (20 mM HEPES, pH 7.4, 0 mM EDTA, EDTA-free complete protease inhibitor cocktail [1 tablet/25 ml]).
- the cell suspension is homogenized on ice, using a Polytron homogenizer at 30000 rpm at three intervals of 15 seconds each.
- the homogenate is first centrifuged at 2000 rpm on a tabletop low speed centrifuge for 10 minutes.
- the supernatant after passing through a cell strainer, is then re-centrifuged at 50,000 x g for 25 minutes at 4 0 C.
- the pellet is resuspended into buffer B (15% glycerol, 20 mM HEPES, pH 7.4, 0.1 mM EDTA, EDTA- free complete protease inhibitor cocktail [1 tablet/10 ml]).
- Protein concentration of the preparation is determined using the BCA Protein Assay kit (Pierce) using BSA as standard.
- the membranes are aliquoted and kept frozen at -80 0 C.
- test compounds ranging from 1OmM to 0.01 nM are prepared in DMSO. S1 P is diluted in 4% BSA solution as positive controls. The desired amount of membrane preparation is diluted with ice-cold assay buffer (20 mM HEPES, pH 7.4, 100 mM NaCI, 10 mM MgCI 2 , 0.1 % Fatty acid-free BSA, 5 ⁇ M GDP) and vortexed well. 2 ⁇ l or less of compound is distributed into each well of a round-bottom 96-well polystyrene assay plate, followed by addition of 100 Gl of diluted membranes (3-10 ⁇ g/well) and kept on ice until the addition of hot GTP ⁇ S.
- ice-cold assay buffer (20 mM HEPES, pH 7.4, 100 mM NaCI, 10 mM MgCI 2 , 0.1 % Fatty acid-free BSA, 5 ⁇ M GDP
- [ 35 S]-GTPyS is diluted 1 :1000 (v/v) with cold assay buffer and 100 ⁇ l is added into each well. The reaction is carried out at room temperature for 90 minutes before the membranes are harvested onto Perkin-Elmer Unifilter ® GF/B-96 filter plate using a Packard Filtermate Harvester. After several washes with wash buffer (20 mM HEPES, pH 7.4, 100 mM NaCI, 10 mM MgCI 2) , and a rinse with 95% ethanol, the filter is dried in a 370C oven for 30 minutes. MicroScint-20 is added and the plate sealed for scintillation counting on TopCount. EC 50 values are obtained by fitting the GTP [ ⁇ - 35 S] binding curves (raw data) with the dose response curve-fitting tool of GraphPad Prism. Six or twelve different concentrations are used to generate a concentration response curve (using three data points per concentration).
- S1 P-2,-3,-4 and -5 GTP [ ⁇ - 35 S] binding assays are carried out in a comparable manner to the S1 P1 GTP [ ⁇ - 3S S] binding assay using membranes from CHO cells stably expressing c- terminal c-myc tagged or untagged receptors. For each membrane preparation , titration experiments are first run with S1 P control to determine the optimal amount of membranes to be added per assay well.
- Compounds of formula I are tested according to the above assay and show binding affinity to to S1 P receptors, e.g. S1 P1 receptors with an EC 50 ⁇ 1 ⁇ M. More particularly, compounds of formula I exhibit selectivity for the S1 P1 receptor.
- Compounds of Examples 21 , 44 and 105 have an EC 50 ⁇ 100 nM in the above S1 P1 receptor binding assay and are at least 20 fold selective for S1 P1 receptor compared to S1 P3 receptor, and at least 20 fold selective for S1 P1 receptor compared to S1 P-5 receptor.
- CHO cells expressing an S1 P receptor are maintained in F-12K medium (ATCC), containing 5% FBS, with 500 ⁇ g/ml of G418. Prior to the assay, the cells are plated in 384 black clear bottom plates at the density of 10,000 cells/well/25 ⁇ l in the medium of F-12K containing 1 % FBS. The second day, the cells are washed three times (25 ⁇ l/each) with washing buffer. About 25 ⁇ l of dye are added to each well and incubated for 1 hour at 37 0 C and 5% CO 2 .
- the cells are then washed four times with washing buffer (25 ⁇ l/each).
- the calcium flux is assayed after adding 25 ⁇ l of SEW2871 (published by Rosen et al., used as reference) solution to each well of cells.
- the same assay is performed with cells expressing each of the different S1 P receptors. Titration in the FLIPR calcium flux assay is recorded over a 3-minute interval, and quantitated as maximal peak height percentage response relative to S1 P-1 activation.
- the compounds of formula I are active in this assay at a concentration of from 10 '12 and 3.10 '5 M.
- Measurement of circulating lymphocytes Compounds to be tested are dissolved in DMSO/PEG200 and further diluted with deionized water. Rats (Lewis strain, female, 6-12 weeks old) are administered 1 mg/kg of compound to be tested in 4 ml/kg vehicle (max. 2% DMSO/max. 2% PEG200/water) via per os application. DMSO/PEG200/water and FTY720 (0.3 mg/kg) are included as negative and positive controls, respectively. Blood is collected from the sublingual vein 2, 6, 24 and 48 hours after administration under short isoflurane anesthesia. Whole blood samples are subjected to hematology analysis. Peripheral lymphocyte counts are determined using an automated analyzer.
- ED 50 which is defined as the effective dose required to display 50 % of. blood lymphocyte depletion.
- Compounds of formula I are tested according to the above assay and have an ED 50 of less than 10 mg/kg.
- the compounds of formula I are, therefore, useful in the treatment and/or prevention of diseases or disorders mediated by lymphocytes interactions, e.g. in transplantation, such as acute or chronic rejection of cell, tissue or organ allo- or xenografts or delayed graft function, graft versus host disease, autoimmune diseases, e.g.
- rheumatoid arthritis systemic lupus erythematosus, hashimotoS thyroidis, multiple sclerosis, myasthenia gravis, diabetes type I or Il and the disorders associated therewith, vasculitis, pernicious anemia, Sjoegren syndrome, uveitis, psoriasis, Graves ophthalmopathy, alopecia areata and others, allergic diseases, e.g. allergic asthma, atopic dermatitis, allergic rhinitis/conjunctivitis, allergic contact dermatitis, inf lammatory diseases optionally with underlying aberrant reactions, e.g.
- inflammatory bowel disease Crohnfs disease or ulcerative colitis
- intrinsic asthma inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunologically-mediated disorders, inflammatory eye disease, keratoconjunctivitis, myocarditis or hepatitis, e.g. acute or chronic hepatitis, ischemia/reperfusion injury, e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, traumatic shock, cancer, e.g.
- T cell lymphomas or T cell leukemias nephrotic syndrome
- infectious diseases e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS, viral hepatitis, e.g. hepatitis B or C, chronic bacterial infection, or neurodegenerative diseases, e.g. Alzheimer disease, amyotrophic lateral sclerosis or senile dementia.
- infectious diseases e.g. toxic shock (e.g. superantigen induced), septic shock, adult respiratory distress syndrome or viral infections, e.g. AIDS, viral hepatitis, e.g. hepatitis B or C, chronic bacterial infection, or neurodegenerative diseases, e.g. Alzheimer disease, amyotrophic lateral sclerosis or senile dementia.
- AIDS viral hepatitis
- hepatitis B or C chronic bacterial infection
- neurodegenerative diseases e.g. Alzheimer
- pancreatic islets stem cells, bone marrow, corneal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus.
- the required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired.
- system ical Iy at daily dosages of from about 0.03 to 5.0 mg/kg per body weight.
- An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 500 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.
- Suitable unit dosage forms for oral administration comprise from ca. 0.1 to 50 mg active ingredient.
- the compounds of formula I may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form.
- Pharmaceutical compositions comprising a compound of formula I in free form or in pharmaceutically acceptable salt form in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
- the compounds of formula I may be administered in free form or in pharmaceutically acceptable salt form e.g. as indicated above.
- Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
- the present invention further provides:
- a method for preventing or treating disorders or diseases mediated by lymphocytes, e.g. such as indicated above, in a subject in need of such treatment comprises administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
- a method for preventing or treating acute or chronic transplant rejection or T-cell mediated inflammatory or autoimmune diseases, e.g. as indicated above, in a subject in need of such treatment comprises administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;
- a compound of formula I in free form or in a pharmaceutically acceptable salt form for use as a pharmaceutical, e.g. in any of the methods as indicated under 1.1 or 1.2 above.
- a pharmaceutical composition e.g. for use in any of the methods as in 1.1 or 1.2 above comprising a compound of formula I in free form or pharmaceutically acceptable salt form in association with a pharmaceutically acceptable diluent or carrier therefore.
- the compounds of formula I may be administered as the sole active ingredient or in conjunction with, e .g. as an adjuvant to, other drugs e.g. im munosuppressive or immunomodulating agents or other anti-inflammatory agents, e.g. for the treatment or prevention of allo- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders, or a chemotherapeutic agent, e.g a malignant cell anti-proliferative agent.
- the compounds of formula I may be used in combination with a calcineurin inhibitor, e.g. cyclosporin A or FK 506; a mTOR inhibitor, e.g.
- rapamycin 40-O-(2-hydroxyethyl)- rapamycin, CCI779, ABT578, AP23573, biolimus-7 or biolimus-9; an ascomycin having immuno-suppressive properties, e.g. ABT-281 , ASM981 , etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid or salt; mycophenolate mofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof; a PKC inhibitor, e.g. as disclosed in WO 02/38561 or WO 03/82859, e.g.
- a PKC inhibitor e.g. as disclosed in WO 02/38561 or WO 03/82859, e.g.
- a JAK3 kinase inhibitor e.g. N-benzyl- 3,4-dihydroxy-benzylidene-cyanoacetamide ⁇ -cyano-(3,4-dihydroxy)-]N-benzylcinnamamide (Tyrphostin AG 490), prodigiosin 25-C (PNU156804), [4-(4'-hydroxyphenyl)-amino-6,7- dimethoxyquinazoline] (WHI-P131 ), [4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7- dimethoxyquinazoline] (WHI-P154), [4-(3',5'-dibromo-4'-hydroxy lpheny l)-amino-6,7- dimethoxyquinazoline] WHI-P97, KRX-211 , 3- ⁇ (3R,4R)-4-methyl-3-[methyl-(
- mono-citrate also called CP-690,550
- CP-690,550 mono-citrate
- immunosuppressive monoclonal antibodies e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or their ligands
- other immunomodulatory compounds e.g. a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g.
- CTLA4 an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y; adhesion molecule inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or a chemotherapeutic agent, e.g. paclitaxel, gemcitabine, cisplatinum, doxorubicin or 5-fluorouracil ; or an anti-infectious agent.
- a non-CTLA4 protein sequence e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y
- adhesion molecule inhibitors e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists
- the compounds of formula I are administered in conjunction with other immunosuppressive / immunomodulatory, anti-inflammatory, chemotherapeutic or anti- infectious therapy
- dosages of the co-administered immunosuppressant, immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infectious compound will of course vary depending on the type of co-drug employed, e.g. whether it is a steroid or a calcineurin inhibitor, on the specific drug employed, on the condition being treated and so forth.
- the present invention provides in a yet further aspect:
- a method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective non-toxic amount of a compound of formula I and at least a second drug substance, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic drug, e.g. as indicated above.
- a second drug substance e.g. an immunosuppressant, immunomodulatory, anti-inflammatory or chemotherapeutic drug, e.g. as indicated above.
- a pharmaceutical combination e.g. a kit, comprising a) a first agent which is a compound of formula I as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent, e.g. an immunosuppressant, immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infectious agent.
- the kit may comprise instructions for its administration.
- co-administrationDor G ⁇ ombined administrationDor the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
- [pharmaceutical combination Das used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
- the term [ ⁇ ixed combinationo means that the active ingredients, e.g. a compound of formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
- the term Oion-fixed combinationG means that the active ingredients, e.g. a compound of formula I and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
- cocktail therapy e.g. the administration of 3 or more active ingredients.
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Abstract
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009529611A JP2010504932A (en) | 2006-09-29 | 2007-09-27 | Oxadiazole derivatives with anti-inflammatory and immunosuppressive properties |
CA002664268A CA2664268A1 (en) | 2006-09-29 | 2007-09-27 | Diaryl oxadiazol derivatives |
EP07818514A EP2081916A1 (en) | 2006-09-29 | 2007-09-27 | Oxadiazole derivatives with anti-inflammatory and immunosuppressive properties |
MX2009003129A MX2009003129A (en) | 2006-09-29 | 2007-09-27 | Oxadiazole derivatives with anti-inflammatory and immunosuppressive properties. |
US12/443,233 US20100087491A1 (en) | 2006-09-29 | 2007-09-27 | Polycyclic compounds |
BRPI0717656-2A2A BRPI0717656A2 (en) | 2006-09-29 | 2007-09-27 | OXADIAZOL DIARYL DERIVATIVES |
AU2007302262A AU2007302262A1 (en) | 2006-09-29 | 2007-09-27 | Oxadiazole derivatives with anti-inflammatory and immunosuppressive properties |
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JP (1) | JP2010504932A (en) |
KR (1) | KR20090057070A (en) |
CN (1) | CN101522646A (en) |
AU (1) | AU2007302262A1 (en) |
BR (1) | BRPI0717656A2 (en) |
CA (1) | CA2664268A1 (en) |
MX (1) | MX2009003129A (en) |
RU (1) | RU2009115963A (en) |
WO (1) | WO2008037476A1 (en) |
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WO2009043889A2 (en) * | 2007-10-04 | 2009-04-09 | Merck Serono S.A. | Oxadiazole derivatives |
WO2009151529A1 (en) | 2008-05-14 | 2009-12-17 | The Scripps Research Institute | Novel modulators of sphingosine phosphate receptors |
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JP2011513381A (en) * | 2008-03-07 | 2011-04-28 | アクテリオン ファーマシューティカルズ リミテッド | Pyridin-2-yl derivatives as immunomodulators |
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WO2011136927A1 (en) | 2010-04-27 | 2011-11-03 | Allergan, Inc. | 3-(4-((1h-imidazol-1-yl)methyl)phenyl)-5-aryl-1,2,4-oxadiazole derivatives as sphingosine-1 phosphate receptors modulators |
WO2012004287A1 (en) * | 2010-07-08 | 2012-01-12 | Merck Serono S.A. | 5-(biphenyl-4-yl)-3-phenyl-1,2,4-oxadiazolyl derivatives as ligands on the sphingosine 1-phosphate (s1p) receptors |
US8288554B2 (en) | 2006-09-08 | 2012-10-16 | Actelion Pharmaceuticals Ltd. | Pyridin-3-yl derivatives as immunomodulating agents |
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US8658675B2 (en) | 2009-07-16 | 2014-02-25 | Actelion Pharmaceuticals Ltd. | Pyridin-4-yl derivatives |
US8835470B2 (en) | 2010-04-23 | 2014-09-16 | Bristol-Myers Squibb Company | Mandelamide heterocyclic compounds |
US9133179B2 (en) | 2011-01-19 | 2015-09-15 | Actelion Pharmaceuticals Ltd. | 2-methoxy-pyridin-4-yl-derivatives |
US9187437B2 (en) | 2010-09-24 | 2015-11-17 | Bristol-Myers Squibb Company | Substituted oxadiazole compounds |
WO2018064356A1 (en) | 2016-09-29 | 2018-04-05 | Celgene International Ii Sarl | Compounds and methods for treating lupus |
US10385043B2 (en) | 2015-05-20 | 2019-08-20 | Idorsia Pharmaceuticals Ltd | Crystalline form of the compound (S)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol |
US10676467B2 (en) * | 2017-06-30 | 2020-06-09 | Washington University | Compositions for binding sphingosine-1-phosphate receptor 1 (S1P1), imaging of S1P1, and methods of use thereof |
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EP2241558A1 (en) * | 2009-04-03 | 2010-10-20 | Merck Serono SA | Oxadiazole derivatives |
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Also Published As
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JP2010504932A (en) | 2010-02-18 |
CN101522646A (en) | 2009-09-02 |
CA2664268A1 (en) | 2008-04-03 |
BRPI0717656A2 (en) | 2014-04-29 |
EP2081916A1 (en) | 2009-07-29 |
KR20090057070A (en) | 2009-06-03 |
MX2009003129A (en) | 2009-04-06 |
US20100087491A1 (en) | 2010-04-08 |
AU2007302262A1 (en) | 2008-04-03 |
RU2009115963A (en) | 2010-11-10 |
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