EP1456186A1 - Derives de piperazine et leur utilisation comme inhibiteurs de phospholipase - Google Patents
Derives de piperazine et leur utilisation comme inhibiteurs de phospholipaseInfo
- Publication number
- EP1456186A1 EP1456186A1 EP02799795A EP02799795A EP1456186A1 EP 1456186 A1 EP1456186 A1 EP 1456186A1 EP 02799795 A EP02799795 A EP 02799795A EP 02799795 A EP02799795 A EP 02799795A EP 1456186 A1 EP1456186 A1 EP 1456186A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- aryl
- compound
- formula
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 85
- 239000003112 inhibitor Substances 0.000 title abstract description 16
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 title description 3
- 108010064785 Phospholipases Proteins 0.000 title description 3
- 102000015439 Phospholipases Human genes 0.000 title description 3
- ZVTQYRVARPYRRE-UHFFFAOYSA-N oxadiazol-4-one Chemical compound O=C1CON=N1 ZVTQYRVARPYRRE-UHFFFAOYSA-N 0.000 claims abstract description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 87
- 238000002360 preparation method Methods 0.000 claims description 63
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 16
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 150000002923 oximes Chemical class 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 claims description 2
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- AGUYLIOPRIJITH-UHFFFAOYSA-N 5-[[4-(4-octadecylpiperazine-1-carbonyl)phenyl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1CN(CCCCCCCCCCCCCCCCCC)CCN1C(=O)C(C=C1)=CC=C1CC1C(=O)NC(=O)S1 AGUYLIOPRIJITH-UHFFFAOYSA-N 0.000 claims 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 1
- 230000002757 inflammatory effect Effects 0.000 abstract description 6
- 230000007170 pathology Effects 0.000 abstract description 5
- 101000983077 Homo sapiens Phospholipase A2 Proteins 0.000 abstract description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 abstract 3
- 101001098256 Homo sapiens Lysophospholipase Proteins 0.000 abstract 1
- 101001096022 Homo sapiens Phospholipase B1, membrane-associated Proteins 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 162
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 120
- 239000000460 chlorine Substances 0.000 description 53
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 51
- 239000000203 mixture Substances 0.000 description 49
- 238000005481 NMR spectroscopy Methods 0.000 description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 24
- 239000003480 eluent Substances 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- 238000002844 melting Methods 0.000 description 22
- 230000008018 melting Effects 0.000 description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 239000003921 oil Substances 0.000 description 20
- 238000010992 reflux Methods 0.000 description 20
- 239000000758 substrate Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000013078 crystal Substances 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 102000004190 Enzymes Human genes 0.000 description 17
- 108090000790 Enzymes Proteins 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 230000000694 effects Effects 0.000 description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000004587 chromatography analysis Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 206010030113 Oedema Diseases 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 230000003110 anti-inflammatory effect Effects 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 101710096328 Phospholipase A2 Proteins 0.000 description 9
- 102100026918 Phospholipase A2 Human genes 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 235000011181 potassium carbonates Nutrition 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 7
- 206010061218 Inflammation Diseases 0.000 description 7
- 150000001299 aldehydes Chemical group 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 150000002825 nitriles Chemical class 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- -1 aryl compound Chemical class 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000001110 calcium chloride Substances 0.000 description 6
- 229910001628 calcium chloride Inorganic materials 0.000 description 6
- 229940117173 croton oil Drugs 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 230000002255 enzymatic effect Effects 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- 150000004665 fatty acids Chemical class 0.000 description 6
- 229960000905 indomethacin Drugs 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical class [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 5
- 239000000679 carrageenan Substances 0.000 description 5
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- 238000001704 evaporation Methods 0.000 description 5
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- 229910052757 nitrogen Inorganic materials 0.000 description 5
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- 238000000746 purification Methods 0.000 description 5
- 239000012047 saturated solution Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 5
- UITVEGAFGYIBSV-UHFFFAOYSA-N 1-octadecylpiperazine Chemical compound CCCCCCCCCCCCCCCCCCN1CCNCC1 UITVEGAFGYIBSV-UHFFFAOYSA-N 0.000 description 4
- ZXWFTUPJHKAEHY-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]acetonitrile Chemical compound BrCC1=CC=C(CC#N)C=C1 ZXWFTUPJHKAEHY-UHFFFAOYSA-N 0.000 description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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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
- C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- 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]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
Definitions
- the present invention relates to new specific inhibitor compounds for secreted non-pancreatic phospholipase A 2 (PLA 2 -snph) group II, their preparation process, compositions containing them and their use in particular in therapy of inflammatory pathologies.
- PKA 2 -snph non-pancreatic phospholipase A 2
- PLA 2 Acting upon the penetration into the body of pathogenic agents (viruses, bacteria, parasites or antigens) or even in response to inflammatory stimuli such as trauma, burns or irradiation, PLA 2 play a pivotal role in the spread and amplification of inflammation. These enzymes catalyze the hydrolysis of phospholipids
- lipid mediators including the platelet activating factor (PAF), leukotrienes and prostaglandins. They are endowed with multiple biological activities (proliferation and cell migration,
- PKA 2 -snph group II 25 secreted non-pancreatic human (PLA 2 -snph) group II plays a central role, probably acting in an autocrine / paracrine way by participating in the production of proinflammatory lipid mediators, stimulating migration and cell proliferation and through its properties antibacterial. In many situations
- the level of circulating PLA 2 -snph is closely correlated with the severity and outcome of the disease. This is the case in septic shock caused by either a gram negative infection, peritonitis, malaria or even aspirin poisoning. In this case, an excessive release of PLA 2 -snp contributes to circulatory collapse,
- PLA 2 -snp accumulates in cartilage, joint and extra-articular matrix, chondrocytes and synovial fluid and the level of circulating enzyme is in accordance with the size and number of inflamed joints.
- PLA 2 -snp is involved in asthma, allergic rhinitis, asbestosis.
- this enzyme is activated by ischemia (its expression is also increased after an ischemic brain shock) and plays an important role in the deposition of high density lipoproteins (it is indeed found to be strongly expressed in the atheroma plaque) suggesting a potential role in atherosclerosis and cardiovascular morbidity.
- PLA 2 -snph group II is not the only secreted PLA 2 present in the human body where the PLA 2 of groups I (pancreas), N (heart, lung) and X (spleen, leukocytes, lung) play also an important role.
- pancreatic PLA 2 has a role physiological primordial since its catalytic activity is responsible for the digestion of lipids of food origin. It is therefore important not to influence this function, this being complicated by the fact that all of these enzymes have a great similarity in their size (13 to 14 kDa), their three-dimensional structure (three oc helices more or less connected by 6 with 8 disulfide bridges) and their dependence on calcium necessary for catalytic activity at concentrations of the order of mM. They also have the same action mechanism based on a relay system of protons which involves several residues of the active site: histidine 48, glycine 30, aspartates 49 and 99 and tyrosines 52 and 73.
- the new family of group II PLA2 selective inhibitor compounds having an inhibitory activity much higher than that shown for previously known compounds, in particular the compounds described in French patent application No. FR 99 06366. supra.
- the new compounds according to the invention are characterized in particular by the presence of a substituted or unsubstituted piperazinyl ring on carbon atoms.
- the compounds according to the invention not only have the selective inhibitory activity on group II PLA 2 while remaining completely inactive on group I pancreatic PLA 2, but also have an in vivo activity greater than that of indometacin.
- the compounds according to the invention have excellent bioavailability when administered orally.
- - D signifies the Z-HET group or the Z ⁇ HET group
- -HET is a 5-membered heterocycle such as oxadiazolone (II) or thiazolidine dione (III) of the following formulas: .4.
- -Z- is chosen from the group consisting of - (CR ⁇ R2) n - and - (CRi ⁇ CR 2 ) n
- n an integer having a value ranging from 1 to 6
- R 2 identical or different, independently of one another represent a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atoms.
- -Z represents -CRi ⁇ , in which Ri represents a hydrogen atom or a linear or branched alkyl group of 1 to 6 carbon atoms; - p is an integer having the value 0 or 1;
- -Y- is chosen from the group consisting of C ⁇ O, SO2 and - (CR3R) m- with m being an integer having a value ranging from 1 to 6, R 3 and R, identical or different, independently represent the one of the other a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atoms.
- - A and B on the piperazine cycle identical or different, independently of one another represent a carbon atom linked to hydrogens, a carbon atom linked both to a hydrogen and to a linear or branched alkyl group having 1 to 3 carbon atoms, or a -C ⁇ O group.
- - q is an integer having the value 0 or 1;
- -W- is chosen from the group consisting of - c -, - 0 - c - and
- H C ; -R is chosen from the group consisting of linear or branched alkyl groups having from 1 to 22 carbon atoms, the polyaryl groups and the aryl-alkyl, alkyl-Q-alkyl, alkyl-Q-aryl, aryl-Q-aryl and aryl-Q-alkyl groups for which:
- aryl represents an aryl group having from 5 to 10 members, it is understood any aryl compound, substituted or unsubstituted, known to those skilled in the art, in particular the phenyl, naphthyl, phenylphenyl (or biphenyl) group or else a heterocyclic aryl such as the indolyl group.
- the aryl group is preferably substituted by one or more halogen atoms, such as F, Cl or Br, or also by groups chosen from CF 3 , OH, MeO and N0 2 .
- alkyl represents a linear or branched alkyl group having from 1 to 12 carbon atoms, and
- Q is selected from the group consisting of -O-, -S-, -NH-, -NRs-, -
- the compounds of formula (I) defined above have a selective inhibitory activity on PLA2 from group II, expressed as the concentration of compound (I) capable of inhibiting 50% of the enzymatic activity (IC50), which is in general less than 1 ⁇ M, often less than 0.5 ⁇ M and for some of these compounds is approximately 0.1 ⁇ M, while the most active of the compounds described in application FR 99 06366 has an inhibitory activity, expressed as an IC50 , 3 ⁇ M.
- a family of preferred compounds according to the invention having a very high inhibitory activity selectively on human PLA 2 of Group II is the family of compounds for which p is equal to 1 and Y represents the group C ⁇ O, groups D, A , B, q, W and R having the meanings defined above.
- the compounds of formula (I) above are chosen from the group consisting of: a) l- [4 ′ - (4,5-dihydro-1,2,4 (4H) -5-oxo-oxadiazol-3-ylmethyl) benzyl] - 4-tetradecyl piperazine b) l- [4 '- (4,5-dihydro-1,2,4 (4H) -5-oxo- oxadiazol-3-ylmethyl) benzoyl] -4-octa decylpiperazine c) l- [4 '- (4,5-dihydro-1,2,4 (4H) -5-oxo-oxadiazol-3-ylmethyl) benzoyl] -2,5-di methyl-4-dodecylpiperazine d) l- [4 '- (4,5-dihydro-1,2,4 (4H) -5-oxo-oxadiazol-3-ylmethyl) benzoyl]
- the present invention also relates to a process for the preparation of the compounds of formula (I) described above.
- the preparation process can be chosen from processes I and II below:
- R, q, W, A, B, p, and Y are defined as above and:
- - Z- is chosen from the group consisting of - (CRiR ⁇ Jn- and - (CRi ⁇ CR2) n - with n being an integer having a value ranging from 1 to 6, Ri and
- R2 identical or different, independently of one another represent a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atoms, or to form the corresponding intermediate oxime, then to subject this oxime cyclization by reaction with a chlorocarbonate (or chloroformate) followed by heating to a temperature sufficient to achieve substantially complete cyclization; a) - Method II: reacting the thiazolidine-2,4-dione on the aldehyde function of the derivative of formula (VII):
- R, q, W, A, B, p and Y are defined as above and, -r is an integer having the value 0 or 1, -U- is chosen from the group consisting of - (CR 6 R7) s - and - (CR ⁇ CR7) S - with s being an integer having a value ranging from 1 to 6 and with R 6 and R 7 , identical or different, representing a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atoms.
- This reaction is carried out in refluxing toluene in the presence of pyridinium benzoate to form the ethylenic derivative (V) as defined above, and followed by a possible reduction of the Z ⁇ C double bond by catalytic hydrogenation (Parr apparatus ) in the presence of 100% black palladium and hydrogen under pressure in absolute ethanol at 50 ° C.
- the starting materials for the above process steps can be prepared according to methods well known to those skilled in the art (see in particular Examples 1 to 6 below).
- the invention also relates to the use of a compound of formula (I) as defined above for selectively inhibiting a group II PLA 2 , preferably in an in vitro test.
- the present invention further relates to a pharmaceutical composition characterized in that it comprises at least one compound of general formula (I) described above in association with at least one excipient chosen from the group consisting of pharmaceutically acceptable excipients.
- a pharmaceutical composition as defined is suitable for daily oral or parenteral administration of an amount of a compound of formula (I) of between 1 ⁇ g and 10 mg and preferably between 1 ⁇ g and 1 mg per kg of weight of the patient.
- a pharmaceutical composition as defined above is suitable for local, preferably topical, daily administration of an amount of a compound of formula (I) of between I ⁇ g and 100 mg and preferably between 100 ⁇ g and 10 mg per kg of patient weight.
- composition according to the invention comprises at least one pharmaceutically acceptable excipient
- it is in particular an excipient suitable for administration of the composition by topical route, an excipient suitable for administration of the composition by oral route and / or an excipient suitable for administration of the composition by the parenteral route.
- the present invention also relates to a compound of general formula (I) as described above, for its use as a therapeutically active principle in a drug.
- the subject of the invention is the use of at least one compound of general formula (I) as described above for the preparation of a medicinal composition intended to inhibit the activity of non-secreted PLA 2 human pancreatic group IL
- the present invention also relates to the use of at least one compound of general formula (I) as described above, for the preparation of a medicament intended for the prevention or treatment of inflammation, in particular of chronic inflammation and acute inflammation, that is to say, in particular inflammatory pathologies in which the non-pancreatic secreted PLA2 is involved.
- the present invention also relates to the use of at least one compound of general formula (I) as described above, for the preparation of a medicament intended for the treatment of rheumatic disorders.
- the invention also relates to a method for treating an inflammation state in a patient, preferably a chronic inflammation state or an acute inflammation state, said method comprising a step during which the patient is administered a therapeutically effective amount of a compound of formula (I) or of a pharmaceutical composition containing a compound of formula (I).
- the subject of the invention is also a method for preventing a state of inflammation in a patient, said method comprising a step during which the patient is administered a therapeutically effective amount of a compound of formula (I) or of a pharmaceutical composition containing a compound of formula (I).
- the compound of formula (I) or the pharmaceutical composition containing the compound of formula (I) can be administered orally, parenterally or even be applied topically, locally to the skin of a patient.
- the following examples are intended to illustrate the present invention and should in no way be interpreted as being capable of limiting its scope.
- N-bromosuccinimide N-bromosuccinimide
- AIBN 2.2'- azobis (2-methyl-piOpionitrile)
- the carbonate intermediate obtained is then taken up in 40 ml of dry toluene and heated for 12 hours at reflux.
- the toluene is then evaporated under reduced pressure and the residue obtained is purified by chromatography on a column of silica gel eluted with a mixture of EfeCfe / MeOH, 98: 2, v / v.
- the product crystallizes from an acetone / ether mixture and leads to 500 mg of white crystals of the terminal compound. Yield: 26%.
- Rf 0.33 (CH 2 Cl 2 / MeOH, 90:10, v / v).
- step 1.4 of Example 1 Following the same protocol as that described for step 1.4 of Example 1, but starting with 1.3 g (2.53 mmol) of amidoxime prepared in the previous step 2.5, 0.45 ml (3 , 28 mmol) of triethylamine as well as 0.4 ml (3.03 mmol) of phenyl chloroformate. The product crystallizes from acetone and leads to 500 mg of white crystals of terminal compound. Yield: 37%. Melting point: 121 ° C. Rf: 0.38 (CH 2 Cl 2 / MeOH, 90:10, v / v).
- step 1.3 of Example 1 Following the same protocol as that described for step 1.3 of Example 1, but starting from 1.52 g (21 mmol) of hydroxylamine hydrochloride, 3.64 g (26 mmol) of potassium carbonate and 2 g (4 mmol) of the nitrile obtained in step 4.3 above.
- the crude product is purified by chromatography on a column of silica gel with dichloromethane as eluent and gives an oil which crystallizes from acetone. 600 mg of white crystals of the title amidoxime are thus recovered. Yield: 28%. Melting point: 110.1 ° C. Rf: 0.40 (CH 2 Cl 2 / MeOH, 95: 5, v / v). 48139
- a suspension of 210 mg (3.69 10 ⁇ 4 mole) of the compound of Example 5, dissolved in 50 ml of absolute ethanol is subjected to catalytic hydrogenation in a Parr apparatus, in the presence of 100% black palladium and of hydrogen under pressure (40 to 50 psi) and stirred for more than 5 hours at 60 ° C.
- the palladium is filtered, the ethanol evaporated and the residue obtained is purified by chromatography on a gel column. silica with a dichloromethane / methanol mixture, 99: 1, v / v as eluent.
- the product is then crystallized from acetonitrile and 126 is recovered.
- the salt formed (ZnCl) is filtered under vacuum and washed several times with water. A precipitate is deposited cold in the filtrate, it is filtered and washed several times with water and then dried. A white solid is recovered. Yield: 68%. Fusion point :
- the bromine derivative prepared above is transformed into nitrile according to the same protocol described in Example 1 above with a yield of 75% and of viscous appearance.
- This amidoxime is obtained under the same conditions as those described above from 5.8 g (84 mmol) of hydroxylamine hydrochloride, 14.07 (102 mmol) of potassium carbonate and 8.9 g (17 mmol) of 1 - (4'-cyanomethylbenzoyl) -4- (octadecylaminocarbonyl) piperazine.
- the residue obtained is purified by chromatography on silica gel with a mixture of CH 2 Cl 2 / MeOH, 98: 2, v / v as eluent. 2.36 g of white crystals are thus obtained. Yield: 38%. Melting point: 104-106 ° C. Rf: 0.43 (CH 2 Cl 2 / MeOH, 90:10, v / v).
- Phospholipases A 2 hydrolyze the ester bond in position sn-2 of the glycerol phospholipids and release a fatty acid and a lysophospholipid.
- the action of the compounds was in particular evaluated in vitro by the determination of fatty acid according to the fluorimetric method of Radvanyi et al. (Anal. Biochem. 1989, 177, 103-109) and by the determination of lysophospholipid according to the UN spectrophotometric method of Reynolds et al. (Anal. Biochem. 1992, 204, 190-197).
- the enzymes used are two secreted group II enzymes, recombinant human PLA 2 and the basic PLA 2 subunit of Crotalus durissus terrificus and a secreted group I enzyme, pig pancreatic PLA 2 .
- the substrates are: a fluorescent substrate, palmitoyl-2- (10-pyrenyl decanoyl) -sn-glycero-3-phosphatidylglycerol acid, for the fluorimetric method and a sulfur substrate, the lithium salt of 1,2-bis - (dihexanylthio) -dideoxy-rac-glycero-3- ⁇ hosphorylglycerol for the spectrophotometric method UN.
- the fluorimetric assays are carried out on a Perkin Elmer LS50 device in single-use polystyrene tanks, 1 cm wide. The exact concentration of the fluorescent substrate is determined on a UN spectrometer. Unicam in quartz tanks.
- PLA2 is an enzyme which hydrolyzes the ester bond in position sn-2 of phospholipids.
- the fluorescent substrate has a maximum fluorescence emission at 490 nanometers (nm), and zero at 398 nm.
- the fluorescence emitted by the fatty acid released (pyrenyl decanoic acid), complexed with bovine serum albumin (SAB) is exalted and a strong emission is then observed at 378 and 398 nm.
- SAB bovine serum albumin
- the principle of the assay is based on the measurement of this difference in fluorescence at 398 nm which is used to study the appearance of the fatty acid released over time, in other words, the PLA2 activity.
- the measurement of the enzymatic activity is carried out in tanks in which we sample: 960 ⁇ l of Tris buffer, 50 mM HCl at pH 7.5; 0.5 M NaCl, EGTA, ImM; 1 ⁇ M substrate. This mixture is stirred for one minute using a vortex, to allow the formation of substrate vesicles, then 10 ⁇ l of 10% BSA, 10 ⁇ l of solvent (efhanol or DMSO) or inhibitor solution, are added successively, with stirring. ⁇ l of PLA2 at a given concentration and finally, 10 ⁇ l of 1 M calcium chloride (CaCl 2 ) which triggers the activity.
- the initial concentrations used are therefore: (i) human recombinant PLA 2 : 0.1 ⁇ g / ml; (ii) PL A 2 pancreatic pork: 0.6 ⁇ g / ml; (iii) PLA 2 Crotalus durissus terrificus (CB): 0.05 ⁇ g / ml.
- the mother solution containing the inhibitor is prepared at an initial concentration of 10 ′ 2 M.
- PLA 2 have more affinity for organized substrates.
- the inhibitor disorganizes the substrate micelles and makes them inaccessible to the enzyme. In this case, the inhibition is due to the unavailability of the substrate.
- the IC50 can be underestimated.
- the inhibitor reacts either with a group of the active site or with another part of the enzyme, thus preventing hydrolysis of the substrate.
- the inhibition observed is real, it takes place at the active site, and may or may not have a reversible character.
- the fluorimetric test is a very sensitive technique, but does not make it possible to differentiate between these three types of inhibition, the substrate being in micellar form.
- the substrate being in micellar form.
- the spectrophotometric test described below, the monomeric state of the substrate 48139
- LTPL lysothiophospholipid released by the lipolytic action of PLA 2 in the presence of calcium reacts with dithionitrobenzoic acid (DTNB) present in the medium to form an LTPL-TNB complex and a TNB- anion which induces a yellow coloration of the reaction medium.
- DTNB dithionitrobenzoic acid
- the measurement of the optical density at 412 nanometers (wavelength of absorption of the TNB- ion) reflects the appearance of the lysothiophospholipid and therefore a PLA 2 activity.
- the enzymatic activity is measured in multi-well plates, each well containing 190 ⁇ l of buffer IX, 2 ⁇ l of DTNB at 10 mM, 2 ⁇ l of substrate at 20 mM, 2 ⁇ l of solvent or inhibitor solution, 2 ⁇ l of PLA 2 at a given concentration.
- the plate is shaken and 2 ⁇ l of 1 M calcium chloride are added to trigger the enzymatic reaction.
- the substrate is used here at a concentration lower than the cmc, critical micellar concentration (it is of ImM), in monomeric form, and the substrate / enzyme ratio is respected. This justifies the use of the substrate at a concentration 5 times lower than the cmc (200 ⁇ M). Good measurement conditions also require enzyme saturation.
- the concentrations used are therefore: (i) pancreatic pig PLA 2 : 1.5 mg / ml; (ii) PLA 2 Crotalus durissus terrificus: 0.43 mg / ml.
- the mother solution containing the inhibitor is prepared at an initial concentration of 10 ' 2 M.
- the IC50 is determined using software coupled to the UN spectrophotometer. It directly calculates the initial rate of the reaction. This speed is represented by the ratio: 048139
- the reference product, indomethacin, or compound No. 5 to be evaluated were administered either intraperitoneally (ip) or orally (po) one hour before the injection of carrageenan in the hind paw of the rat.
- the volume of the edema was measured at times 0, 3 and 5 hours after the injection of carrageenan.
- the doses used were 5, 10 and 20 mg / kg for the two products tested. 048139
- the two products have equivalent activity.
- the inhibitions of edema by indomethacin and compound No. 5 are 79% and 73% respectively.
- compound No. 5 has a clearly superior activity to that of indomethacin since, after 5 hours after the injection of carrageenan, it inhibits edema by 65%, while the reference product has an inhibitory activity of 16%, the two products having been administered at a dose of 10 mg / kg po
- Example 13 relates to a study of the anti-inflammatory activity in vivo of certain compounds of the invention, by means of the test of ear edema as an experimental model of acute inflammation.
- PMS1289 1- para ((1,2,4- (4H) -5-oxo) oxodiazol-3-ylmethyl) benzoyl) 4-dodecyl-2,5-dimethylpiperazine.
- PMS 1314 1- [4 '- (4,5-dihydiO-1,2,4 (4H) -5-oxo-oxadiazol-3-ylmethyl) benzoyl] - 4-dodecylpiperazine.
- CMC cyclopentane
- ethanol hexane
- ether hexane
- PEG polyethylene glycol
- the animals used were male mice of the ICR strain having a weight of 25 g.
- A3 As instruments, we used: a punch for taking skin samples, an ear thickness measuring device (Ozaki, Japan), a balance, an automatic pipette, tweezers, a Nortex shaker, a anesthesia chamber, hood, cage, Eppendorf ® tube, safety mat, tubes etc.
- the weight of the tissue developing an edema was taken by punching the skin and compared with a sample by punching the skin of a control part in order to calculate the inhibition ratio. .
- the anti-inflammatory activities in vivo of the PMS compounds are classified from the 048139
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- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Description
Claims
Applications Claiming Priority (3)
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FR0115798 | 2001-12-06 | ||
FR0115798A FR2833261B1 (fr) | 2001-12-06 | 2001-12-06 | Nouveaux composes inhibiteurs specifiques de la phospholipase a2 secretee non pancreatique humaine du groupe ii |
PCT/FR2002/004225 WO2003048139A1 (fr) | 2001-12-06 | 2002-12-06 | Derives de piperazine et leur utilisation comme inhibiteurs de phospholipase |
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EP1456186A1 true EP1456186A1 (fr) | 2004-09-15 |
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EP02799795A Withdrawn EP1456186A1 (fr) | 2001-12-06 | 2002-12-06 | Derives de piperazine et leur utilisation comme inhibiteurs de phospholipase |
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US (1) | US20050075345A1 (fr) |
EP (1) | EP1456186A1 (fr) |
JP (1) | JP2005511689A (fr) |
KR (1) | KR20050044694A (fr) |
CN (1) | CN1612868A (fr) |
AU (1) | AU2002364435A1 (fr) |
CA (1) | CA2469395A1 (fr) |
FR (1) | FR2833261B1 (fr) |
WO (1) | WO2003048139A1 (fr) |
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US20050119251A1 (en) * | 2001-12-21 | 2005-06-02 | Jian-Min Fu | Nicotinamide derivatives and their use as therapeutic agents |
CN101083992A (zh) | 2004-09-20 | 2007-12-05 | 泽农医药公司 | 抑制人硬脂酰CoA去饱和酶的哒嗪衍生物 |
MX2007003327A (es) | 2004-09-20 | 2007-06-05 | Xenon Pharmaceuticals Inc | Derivados heterociclicos, y su uso como mediadores de estearoil-coa desaturasa. |
EP2269610A3 (fr) | 2004-09-20 | 2011-03-09 | Xenon Pharmaceuticals Inc. | Dérivés hétérocycliques et leur utilisation en tant qu'inhibiteurs de la stearoyl-coa desaturase |
TW200626148A (en) * | 2004-09-20 | 2006-08-01 | Xenon Pharmaceuticals Inc | Heterocyclic derivatives and their use as therapeutic agents |
AR051092A1 (es) | 2004-09-20 | 2006-12-20 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como inhibidores de la estearoil-coa |
TW200626138A (en) | 2004-09-20 | 2006-08-01 | Xenon Pharmaceuticals Inc | Heterocyclic derivatives and their use as therapeutic agents |
CA2580787A1 (fr) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Derives heterocycliques et utilisation de ceux-ci comme agents therapeutiques |
AU2005286648A1 (en) * | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors |
CA2618646A1 (fr) * | 2005-06-03 | 2007-11-15 | Xenon Pharmaceuticals Inc. | Derives aminothiazole utilises en tant qu'inhibiteurs de la stearoyle-coa desaturase humaine |
DE602007011793D1 (de) * | 2006-10-18 | 2011-02-17 | Pfizer Prod Inc | Biaryl-ether-harnstoffverbindungen |
GB0813144D0 (en) | 2008-07-17 | 2008-08-27 | Glaxo Group Ltd | Novel compounds |
GB0813142D0 (en) | 2008-07-17 | 2008-08-27 | Glaxo Group Ltd | Novel compounds |
WO2011160043A2 (fr) | 2010-06-18 | 2011-12-22 | Whitehead Institute For Biomedical Research | Pla2g16 utilisé en tant que cible pour des composés antiviraux |
EP2923710A1 (fr) | 2014-03-27 | 2015-09-30 | Universitätsklinikum Heidelberg | Inhibiteurs de phospholipase bactérienne en tant que modulateurs de la flore bactérienne du côlon |
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FR2793791B1 (fr) * | 1999-05-19 | 2002-01-25 | Univ Paris 7 Denis Diderot | Nouveaux composes inhibiteurs specifiques de phospholipases a2 |
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2001
- 2001-12-06 FR FR0115798A patent/FR2833261B1/fr not_active Expired - Fee Related
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2002
- 2002-12-06 CN CNA028266633A patent/CN1612868A/zh active Pending
- 2002-12-06 AU AU2002364435A patent/AU2002364435A1/en not_active Abandoned
- 2002-12-06 EP EP02799795A patent/EP1456186A1/fr not_active Withdrawn
- 2002-12-06 KR KR1020047008597A patent/KR20050044694A/ko not_active Application Discontinuation
- 2002-12-06 CA CA002469395A patent/CA2469395A1/fr not_active Abandoned
- 2002-12-06 JP JP2003549331A patent/JP2005511689A/ja active Pending
- 2002-12-06 US US10/497,742 patent/US20050075345A1/en not_active Abandoned
- 2002-12-06 WO PCT/FR2002/004225 patent/WO2003048139A1/fr not_active Application Discontinuation
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FR2833261A1 (fr) | 2003-06-13 |
JP2005511689A (ja) | 2005-04-28 |
US20050075345A1 (en) | 2005-04-07 |
CA2469395A1 (fr) | 2003-06-12 |
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KR20050044694A (ko) | 2005-05-12 |
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