WO2003097575A2 - Amino-functional chalcones - Google Patents
Amino-functional chalcones Download PDFInfo
- Publication number
- WO2003097575A2 WO2003097575A2 PCT/DK2003/000331 DK0300331W WO03097575A2 WO 2003097575 A2 WO2003097575 A2 WO 2003097575A2 DK 0300331 W DK0300331 W DK 0300331W WO 03097575 A2 WO03097575 A2 WO 03097575A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- propenone
- optionally substituted
- dimethylaminomethyl
- methyl
- Prior art date
Links
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 235000005513 chalcones Nutrition 0.000 title claims abstract description 36
- 150000001789 chalcones Chemical class 0.000 title abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 313
- 238000000034 method Methods 0.000 claims abstract description 215
- 239000000203 mixture Substances 0.000 claims abstract description 75
- 241000894006 Bacteria Species 0.000 claims abstract description 48
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 10
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
- -1 cyano, guanidino Chemical group 0.000 claims description 109
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 59
- 125000001424 substituent group Chemical group 0.000 claims description 55
- 230000000694 effects Effects 0.000 claims description 47
- 229910052736 halogen Inorganic materials 0.000 claims description 43
- 150000002367 halogens Chemical class 0.000 claims description 42
- 125000001072 heteroaryl group Chemical group 0.000 claims description 39
- 238000011282 treatment Methods 0.000 claims description 35
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 29
- 208000015181 infectious disease Diseases 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 24
- 125000003107 substituted aryl group Chemical group 0.000 claims description 24
- 108010052167 Dihydroorotate Dehydrogenase Proteins 0.000 claims description 20
- 102100032823 Dihydroorotate dehydrogenase (quinone), mitochondrial Human genes 0.000 claims description 20
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 20
- 125000004104 aryloxy group Chemical group 0.000 claims description 20
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 125000001769 aryl amino group Chemical group 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 241000223960 Plasmodium falciparum Species 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 241000590002 Helicobacter pylori Species 0.000 claims description 15
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 15
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 15
- 229940037467 helicobacter pylori Drugs 0.000 claims description 15
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 15
- 125000003282 alkyl amino group Chemical group 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 13
- 241000588724 Escherichia coli Species 0.000 claims description 12
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 241001148471 unidentified anaerobic bacterium Species 0.000 claims description 11
- 241000222722 Leishmania <genus> Species 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 10
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 10
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 10
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- GVSPXQVUXHMUMA-MDWZMJQESA-N (e)-3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GVSPXQVUXHMUMA-MDWZMJQESA-N 0.000 claims description 7
- 241000194031 Enterococcus faecium Species 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 230000001717 pathogenic effect Effects 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 claims description 6
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 241000606124 Bacteroides fragilis Species 0.000 claims description 5
- 241000193996 Streptococcus pyogenes Species 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 5
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000005493 quinolyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 241000193403 Clostridium Species 0.000 claims description 4
- 241000192125 Firmicutes Species 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 230000002255 enzymatic effect Effects 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 230000009278 visceral effect Effects 0.000 claims description 4
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 3
- 241000588921 Enterobacteriaceae Species 0.000 claims description 3
- 208000012895 Gastric disease Diseases 0.000 claims description 3
- 241000223821 Plasmodium malariae Species 0.000 claims description 3
- 241001505293 Plasmodium ovale Species 0.000 claims description 3
- 241000223810 Plasmodium vivax Species 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 244000005700 microbiome Species 0.000 claims description 3
- 229940118768 plasmodium malariae Drugs 0.000 claims description 3
- RAIHTKTZGNUKBB-UHFFFAOYSA-N 1-(2,4-dichlorophenyl)-3-[2-[(dimethylamino)methyl]phenyl]propan-2-one Chemical compound CN(C)CC1=CC=CC=C1CC(=O)CC1=CC=C(Cl)C=C1Cl RAIHTKTZGNUKBB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 2
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 1
- 244000045947 parasite Species 0.000 abstract description 19
- 150000001788 chalcone derivatives Chemical class 0.000 abstract description 12
- 230000002503 metabolic effect Effects 0.000 abstract description 10
- 230000001580 bacterial effect Effects 0.000 abstract description 9
- 208000030852 Parasitic disease Diseases 0.000 abstract description 6
- 239000003096 antiparasitic agent Substances 0.000 abstract description 6
- 229940088679 drug related substance Drugs 0.000 abstract description 5
- 239000003899 bactericide agent Substances 0.000 abstract description 4
- 230000002141 anti-parasite Effects 0.000 abstract description 3
- 241000233866 Fungi Species 0.000 abstract description 2
- 239000013543 active substance Substances 0.000 abstract description 2
- 230000004071 biological effect Effects 0.000 abstract description 2
- 244000000013 helminth Species 0.000 abstract description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 136
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 136
- 239000013078 crystal Substances 0.000 description 107
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 101
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 94
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 68
- 239000000243 solution Substances 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000003921 oil Substances 0.000 description 48
- 235000019198 oils Nutrition 0.000 description 48
- 238000012360 testing method Methods 0.000 description 40
- DKQIZRNNADMWTR-UHFFFAOYSA-N 3-(2-aminophenyl)-1-phenylprop-2-en-1-one Chemical class NC1=CC=CC=C1C=CC(=O)C1=CC=CC=C1 DKQIZRNNADMWTR-UHFFFAOYSA-N 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 36
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 28
- KAZSKMJFUPEHHW-UHFFFAOYSA-N (2E)-3-[5-(1,1-dimethyl-2-propenyl)-4-hydroxy-2-methoxyphenyl]-1-(4-hdyroxyphenyl)-2-propen-1-one Natural products COC1=CC(O)=C(C(C)(C)C=C)C=C1C=CC(=O)C1=CC=C(O)C=C1 KAZSKMJFUPEHHW-UHFFFAOYSA-N 0.000 description 26
- KAZSKMJFUPEHHW-DHZHZOJOSA-N Licochalcone A Chemical compound COC1=CC(O)=C(C(C)(C)C=C)C=C1\C=C\C(=O)C1=CC=C(O)C=C1 KAZSKMJFUPEHHW-DHZHZOJOSA-N 0.000 description 26
- IUCVKTHEUWACFB-UHFFFAOYSA-N Licochalcone A Natural products COC1=CC=C(C(C)(C)C=C)C=C1C=CC(=O)C1=CC=C(O)C=C1 IUCVKTHEUWACFB-UHFFFAOYSA-N 0.000 description 26
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 238000003556 assay Methods 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
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- 229910052786 argon Inorganic materials 0.000 description 15
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 14
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- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
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- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 12
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- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
- C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/44—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reduction and hydrolysis of nitriles
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- C07C47/00—Compounds having —CHO groups
- C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
- C07C47/277—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
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- C07C47/00—Compounds having —CHO groups
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- C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
- C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
- C07D317/66—Nitrogen atoms not forming part of a nitro radical
Definitions
- the present invention relates to a novel class of chalcone derivatives and analogues thereto as well as to use of a class of chalcone derivatives as pharmaceutically active agents, in particular against bacterial and parasitic infections.
- the invention relates to a method of predicting whether a chemical compound has a potential inhibitory effect against an organism such as Helicobacter pylori and Plasmodium falcipar ⁇ m.
- the prediction is based on the ability of the chemical compound to act as an inhibitior of the enzyme dihydroorotate dehydrogenase which is involved in the synthesis of pyrimidine in prokaryotic as well as eukaryotic cells such as bacteria, parasites, fungi, helminths and any type of mammalian cells such as human cells.
- Chalcones for use against parasitic infections are known from earlier patent applications assigned to the applicant, e.g. WO 93/17671 and WO 99/00114. Moderate antibacterial activity has been reported for a limited number of chalcones in earlier publications e.g. Haraguchi, H. et al Phytochemistry 1998, 48, 125-129 and Hatano, T. et al Chem. Pharm. Bull (Tokyo) 2000,48, 1286-92.
- the bioavailability of several of the known chalcones is low due to the low solubility of the compounds.
- the compounds do not typically dissolve in the intestine and are therefore not available for absorption.
- resistant pathogens include Staphylococc ⁇ s aureus resistant to metbicillin and thus to all ⁇ -lactam-antibiotics and Enterococci resistant to vancomycin (VRE).
- VRE vancomycin
- Such resistant bacteria pose a significant therapeutic challenge and bacterial strains resistant to all currently available antimicrobials are emerging.
- bacterial species intrinsically resistant to commonly employed antimicrobials are being recognized as important opportunistic pathogens in the setting of long-term irnmunocompromized patients.
- Stenotrophomonas maltophilia which possesses a ⁇ -lactamase rendering the bacteria intrinsically resistant to carbapenems.
- cross-resistance within a given class of antibiotics often occurs the development of new classes of antibiotics is a neccisity to counter the emerging threat of bacterial resistance.
- Figure 1 illustrates the general synthetic scheme for the preparation of amino-functional chalcones where the aromatic rings are phenyl rings.
- R 1 , R 2 , and Z are as defined herein.
- FIG. 2 illustrates the synthesis of amino-dihydrochalcones.
- R 1 , R 2 , and Z are as defined herein.
- FIG 5 illustrates a dose-response curve of Licochalcone A (LicA) and one of the novel amino-chalcones (A139) at Plasmodium falciparum. As shown at the figure, A139 is 18 times more potent than LicA.
- Figure 6 illustrates a dose-respons curve of LicA and one of the novel amino-chalcones A037 at Leishmania Major. As shown at the figure, A037 is 46 times more potent than LicA.
- Figure 7 illustrates an effect curve of A027 in Plasmodium berghei K173 infected NMRI female mice following multiple intra venous administrations. As shown at the figure, treatment with A027 causes a significant decrease in the parasitaemia.
- Figure 8 illustrates an effect curve of A027 in Plasmodium berghei K173 infected NMRI female mice following multiple oral administrations. As shown at the figure, treatment with A027 causes a significant decrease in the parasitaemia.
- amino-functional chalcones defined herein exhibit interesting biological properties combined with improved metabolic and physicochemical properties which make the compound useful as drug substances, in particular as antiparasitic agents, bacteriostatic agents, and bacteriocidal agents.
- the amino group or groups of the amino-functional chalcone will be charged according to pH of the medium and the pKa of the compound.
- the solubility of the charged compounds is significantly higher than the solubility of the neutral compounds.
- the amino-functional chalcones will be partially charged and thus soluble in aqueous solutions at physiological pH values in the intestine or stomach, they will dissolve in the gastric juices and then be available for absorption.
- the bioavailability of the amino- functional chalcones will therefore be improved compared to the known neutral chalcones, thus making the compounds generally useful as drug candidates.
- the present amino- functional chalcones possess different pKa values which allows the selection of a chalcone derivative with optimal charged/non-charged ratio at a given pH value.
- the amino-functional chalcones defined herein are far more potent against malaria and leishmania parasites than the earlier described neutral chalcone compounds, and that they exhibit excellent bacteriocidal and bacteriostatic properties, even against multi-resistant bacteria strains.
- the present invention provides chalcone derivatives and analogues of the general formula:
- n 0, 1, or 2
- p 0, 1, or 2
- each Y 1 is independently selected from an amino-functional substituent of the formula
- each Y 2 is independently selected from an amino-functional substituent of the formula
- R 1 and R 2 independently may be selected from hydrogen, optionally substituted - ⁇ -alkyl, optionally substituted C 2 - ⁇ 2 -alkenyl, optionally substituted C 4 - 12 -alkadienyl, optionally substituted C 6 - 12 -alkatrienyl, optionally substituted C 2 .
- R 1 and R 2 together with the nitrogen atom to which they are attached (-N(R ⁇ )R 2 ) form an optionally substituted nitrogen-containing heterocyclic ring;
- X 1 and X 2 independently may designate 0-5, preferably 0-4, such as 0-3, e.g. 0-2, substituents, where such optional substituents independently may be selected from optionally substituted - ⁇ -alkyl, optionally substituted C 2 - 12 -alkenyl, optionally substituted C 4 - 12 -alkadienyl, optionally substituted C 6 .
- Cj- ⁇ -alkyl may be substituted with hydroxy, C ⁇ - 6 -alkoxy, C 2 - 6 -aIkenyloxy, amino, mono- and d d-e-alky amino, carboxy, C ⁇ - 6 - alkylcarbonylamino, halogen, Ci- 6 -alkylthio, d- ⁇ -alkyl-sulphonyl-amino, or guanidine;
- the substituents R 1 and R 2 carried by the nitrogen atom of the amino substituent are believed to slightly alter the pKa value of the chalcone derivative.
- the particular selection of the groups R 1 and R 2 may be used to "fine-tune" the pKa value in view of the particular condition or disease and the intended route of administration.
- R 1 and R 2 may be independently selected from hydrogen, optionally substituted C ⁇ _ 12 -alkyl, optionally substituted C 2 - ⁇ 2 -alkenyl, optionally substituted C 2 - 12 - alkynyl, optionally substituted C 1 . 12 -alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, amino- carbonyl, mono- and d C t -e-alkyOaminocarbonyl, amino-Ci- 6 -alkyl-aminocarbonyl, and mono- and di(C 1 . 6 -alkyl)amino-C 1 - 6 -alkyl-aminocarbonyI.
- R 1 and R 2 are independently selected from hydrogen, optionally substituted Q- 6 -alkyl, optionally substituted Ci- ⁇ -alkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, mono- and di(C ⁇ - 6 - alkyl)aminocarbonyl, amino-d- 6 -alkyl-aminocarbonyl, or mono- and d Ci-e-alkyOamino- C ⁇ . 5 -alkyl-aminocarbonyl.
- R 1 and R 2 together with the nitrogen atom to which they are attached form an optionally substituted nitrogen-containing heterocyclic ring.
- X 1 and X 2 independently may designate 0-4, such as 0-3, e.g. 0-2, substituents, where such optional substituents independently may be selected from optionally substituted d- ⁇ -alkyl, hydroxy, optionally substituted d- ⁇ -alkoxy, optionally substituted C 2 .
- halogen where any nitrogen-bound d- 6 -alkyl may be substituted with hydroxy, C ⁇ - 6 - alkoxy, and/or halogen, in particular X 1 and X 2 independently designates 0-3, e.g. 0-2, substituents, where such optional substituents independently are selected from optionally substituted C ⁇ - 6 -alkyl, hydroxy, optionally substituted d- 6 -alkoxy, carboxy, optionally substituted d- 6 _ alkylcarbonyl, C ⁇ _ 6 -alkyIsulphonylamino, optionally substituted aryl,
- X 1 and X 2 independently designates 0-5, preferably 0-4, such as
- substituents where such optional substituents independently are selected from optionally substituted d- 12 -alkyl, optionally substituted C 2 . 12 -alkenyl, optionally substituted C - 12 -alkadienyl, optionally substituted C 6 - 12 -alkatrienyl, optionally substituted d- 12 -alkynyl, hydroxy, optionally substituted d- 12 -alkoxy, optionally substituted C 2 . 12 - alkenyloxy, carboxy, optionally substituted C ⁇ _ 12 -alkoxycarbonyl, optionally substituted d-
- heteroarylamino optionally substituted (heteroarylalkyl)amino, optionally substituted (heteroarylalkyl)alkylamino, heteroarylsulphonylamino, optionally substituted heterocyclyloxycarbonyl, optionally substituted heterocyclyloxy, optionally substituted heterocyclylcarbonyl, optionally substituted heterocyclylamino, heterocydylsulphonylamino, amino, mono- and di(d- 6 -alkyl)amino, carbamoyl, mono- and
- di(C ⁇ - 5 -alkyl)aminocarbonyl amino-d- 6 -alkyl-aminocarbonyl, mono- and di(d-e- alky amino-C ⁇ ⁇ -alkyl-aminocarbonyl, d- ⁇ -alkylcarbonylamino , cyano, guanidino, carbamido, d-e-alkanoyloxy, d- 6 -alkylsulphonyl, d.
- X 1 and X 2 independently may designate 0-3, e.g. 0-2, substituents, where such optional substituents may independently be selected from optionally substituted C ⁇ - 6 -alkyl, hydroxy, optionally substituted d- 6 -alkoxy, carboxy, optionally substituted d- 6 -alkylcarbonyl, d- 6 -alkylsulphonylamino, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylamino, amino, mono- and di(C ⁇ - 6 -alkyl)amino, arylsulphonylamino, optionally substituted heteroaryl, optionally substituted heteroarylamino, optionally substituted (heteroarylalkyl)amino, optionally substituted (heteroarylalkyl)alkylamino, heteroarylsulphonylamino, carbamoyl, d_ 6 -alkyl- carbony
- the group V is relevant with respect to the spatial orientation of the rings Ar 1 and Ar 2 .
- Ar 1 and Ar 2 are selected from aromatic rings and heteroaromatic rings.
- particularly interesting compounds are those where at least one of Ar 1 and Ar 2 , preferably both, are aryl, in particular phenyl.
- the inventors envisage that the functionality of the compounds may be substantially preserved (or even improved) when one or both of Ar 1 and Ar 2 are heteroaromatic rings.
- At least one of Ar 1 and Ar 2 is selected from thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, quinolyl, isoquinolyl, and indolyl.
- both of Ar 1 and Ar 2 are phenyl rings and Y 1 represent at least one amino-functional substituent, i. e. m is 1 or 2, and p is 0.
- X 2 represents at least one substituent selected from d- 6 -alkyl, d- 6 -alkoxy, d- 6 -alkylcarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylamino, optionally substituted heteroaryl, optionally substituted heteroarylamino, optionally substituted (heteroarylalkyl)amino, optionally substituted (heteroarylalkyl)alkylamino, mono- and di(d.
- X 2 represents at least one substituent selected from C ⁇ - 6 - alkyl, d- 6 _ alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylamino, optionally substituted heteroaryl, optionally substituted heteroarylamino, optionally substituted (heteroarylalkyl)amino, optionally substituted 5 (heteroarylalkyl)alkylamino, mono- and di(d- 6 -alkyl)amino, optionally substituted heterocyclyl and halogen.
- the Z group represents the biradical between the ring and the amino functionality.
- a particular example of Z is -(CH 2 ) n - wherein n is 1-4, such as 1-3.
- one of Y 1 and Y 2 represent a substituent of the formula
- R 1 and R 2 is selected from hydrogen and C ⁇ - 6 -alkyl.
- Y 1 represents 20 the substituent fo the formula -CH 2 -N(R 1 )R 2 .
- n is 1 and p is 0. In another preferred embodiment m is 0 and p is 1. In a further interesting embodiment, m and p are both 1.
- Z is CH 2
- R 1 and R 2 are methyl or together form a morpholino group
- one of m and p is 2 while the other of m and p is 0,
- X 1 and X 2 independently may designate 0-5, preferably 0-4, such as 0-3, e.g. 0-2, 30 substituents, where such optional substituents may independently be selected from optionally substituted C 1 . 12 -alkyl, optionally substituted C 2 . 12 -alkenyl, optionally substituted C - 12 -alkadienyl, optionally substituted C 6 - ⁇ 2 -alkatrienyl, optionally substituted C 2 _ ⁇ 2 -alkynyl, 2-, 3-, 5-, or 6-hydroxy, optionally substituted d- 12 -alkoxy, optionally substituted C 2 . 12 - alkenyloxy, carboxy, optionally substituted d-.
- Generally preferred compounds may, e.g., be selected from the group comprising:
- the invention further provides combinatorial libraries, mixtures and kits for screening compounds as defined above.
- a combinatorial library comprising at least two compounds of the general formula.
- Such library may be in the form of an equimolar mixture, or in a mixture of any stoichiometry.
- Typical embodiments comprise at least two, such as at least 10, such as at least 100, such as at least 1000, such as at least 10000, such as at least 100000 compounds as defined above.
- kits for screening for biologically or pharmacologically active compounds comprise at least two topologically distinct singular compounds of the general formula defined above.
- Typical kits comprise at least 10, such as at least 100, such as at least 1000, such as at least 10000, such as at least 100000 compounds as defined above. Kits are preferably provided in the form of solutions of the compounds in appropriate solvents.
- kits or libraries comprising at least two compounds of the general formula defined above, contacting said kit or library with a target molecule, such as a protein or nucleic acid, a target tissue, or a target organism, such as a bacterium or parasite, and detecting a biological or pharmacological response caused by at least one compound.
- a target molecule such as a protein or nucleic acid, a target tissue, or a target organism, such as a bacterium or parasite
- the steps may be repeated as appropriate to achieve deconvolution.
- bacteriostatic is intended to describe an antimicrobial activity of a test compund, characterized by an inhibition of bacterial growth in the absence of a reduction of viable bacteria (bacterial kill) during incubation with the test compound, as evidenced in the killing curve determination by a stationary number of colony forming units (CFU) during incubation time.
- CFU colony forming units
- bacteriocidal is intended to describe an antimicrobial activity of a test compound, characterized by the reduction of viable bacteria (bacterial kill) during incubation with the test compound, as evidenced in the killing curve determination by a reduction of colony forming units (CFU) during incubation time.
- viable bacteria bacterial kill
- CFU colony forming units
- antiparasitic is intended to describe the ability of a test compound to upon incubation in vitro with a culture of parasites, e.g. Leishmania major or Plasmodium falciparum, to inhibit metabolic labelling of the parasites by at least 50% compared to mock treated control cultures.
- a culture of parasites e.g. Leishmania major or Plasmodium falciparum
- C 1 - 12 -alkyl is intended to mean a linear, cyclic or branched hydrocarbon group having 1 to 12 carbon atoms, such as methyl, ethyl, propyl, tso-propyl, cyclopropyl, butyl, tert-butyl, /so-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, etc.
- C ⁇ - 6 -alkyl is intended to mean a linear, cyclic or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, /so-propyl, pentyl, cyclopentyl, hexyl, cyclohexyl
- d- 4 -alkyl is intended to cover linear, cyclic or branched hydrocarbon groups having 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, /so-propyl, cyclopropyl, butyl, /so-butyl, fert-butyl, cyclobutyl.
- C 2 - 12 -alkenyl is intended to cover linear, cyclic or branched hydrocarbon groups having 2 to 12, 4 to 12, and 6 to 12, carbon atoms, respectively, and comprising one, two, and three unsaturated bonds, respectively.
- alkenyl groups are vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, heptadecaenyl.
- alkadienyl groups are butadienyl, pentadienyl, hexadienyl, heptadienyl, heptadecadienyl.
- alkatrienyl groups are hexatrienyl, heptatrienyl, octatrienyl, and heptadecatrienyl.
- alkenyl are vinyl, allyl, butenyl, especially allyl.
- d- 1 2-alkynyl is intended to mean a linear or branched hydrocarbon group having 2 to 12 carbon atoms and comprising a triple bond. Examples hereof are ethynyl, propynyl, butynyl, octynyl, and dodecaynyl.
- C 2 - ⁇ 2 -alkenyl “C 4 - 12 -alkadienyl”, “C 6 . 12 -alkatrienyl”
- C 2 - 12 - alkynyl it should be understood that a particularly interesting embodiment thereof are the variants having up to six carbon atoms.
- alkyl alkenyl
- alkadienyl alkadienyl
- alkatrienyl alkynyl
- alkynyl optionally substituted
- the substituents are selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), d- 6 -alkoxy (i.e. d- 5 -alkyl-oxy), C 2 - 6 _ alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Cj-e-alkylcarbonyl, formyl, aryl, aryloxy, arylamino, arylcarbonyl, heteroaryl, heteroarylamino, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(d- 6 - alkyl)amino; carbamoyl, mono- and di(C ⁇ - 6 -alkyl)aminocarbonyl, amino-d- 6 -alkyl- aminocarbonyl, mono- and di(C ⁇ - 6 -alkyl)amino-C 1 - 6 -alkyl-amino
- Especially preferred examples are hydroxy, d- 6 -alkoxy, C 2 - 6 -alkenyloxy, amino, mono- and di(d- 6 -alkyl)amino, carboxy, d- 6 -alkylcarbonylamino, halogen, d- 6 -alkylthio, d- 6 -alkyl- sulphonyl-amino, and guanidine.
- alkoxy groups may be substituted one or several times, preferably 1-3 times, with group(s) selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), C ⁇ _ 6 -alkoxy (i.e. Cj-e-alkyl-oxy), C 2 .
- Halogen includes fluoro, chloro, bromo, and iodo.
- aryl is intended to mean a fully or partially aromatic carbocydic ring or ring system, such as phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is a preferred example.
- heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, coumaryl, furyl, thienyl, quinolyl, benzothiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl, phenoxazonyl.
- heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, indolyl in particular pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, thienyl, quinolyl, tetrazolyl, and isoquinolyl.
- heterocyclyl groups examples include imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, and hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane, oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothiophene, tetrahydr
- the substituents are selected from hydroxy, C ⁇ - 6 -alkyl, C ⁇ - 5 -alkoxy, oxo (which may be represented in the tautomeric enol form), carboxy, d- 6 -alkylcarbonyl, formyl, amino, mono- and di(d- 6 -alkyl)amino; carbamoyl, mono- and di(d- 6 -alkyl)aminocarbonyl, amino-d- 6 -alkyl-aminocarbonyl, d- ⁇ -alkylcarbonylamino, guanidino, carbamido, d- 6 -alkyl- sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino, C ⁇ - 6 -alkyl-suphonyl, d- 6 -alkyl-sulphinyl, d- 6 -alkyl
- d- 5 -alkyl, C ⁇ - 6 - alkoxy, amino, mono- and di(C 1 - 6 -alkyl)amino, sulphanyl, carboxy or halogen where any alkyl, alkoxy and the like representing substituents may be substituted with hydroxy, d- 6 - alkoxy, C 2 . 6 -alkenyloxy, amino, mono- and di(d- 6 -alkyl)amino, carboxy, d- 6 -alkylcarbony- lamino, halogen, C ⁇ - 6 -alkylthio, d- 6 -alkyl-sulphonyl-amino, or guanidine.
- nitrogen-containing heterocyclic ring is intended to mean heterocyclic ring or ring system in which at least one nitrogen atom is present. Such a nitrogen is, with reference to the formula, carrying the substituents R ⁇ and R 2 .
- rings are aromatic rings such as pyridine, pyridazine, pyrimidine, pyrazine, triazine, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrrole, imidazole, pyrazole, tetrazole, quinoline, benzothiazole, benzotriazole, benzodiazole, benzoxozole, triazole, isoquinoline, indole, benzopyrazole, thiadiazole, and oxadiazole.
- aromatic rings such as pyridine, pyridazine, pyrimidine, pyrazine, triazine, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrrole, imidazole, pyrazole, tetrazole, quinoline, benzothiazole, benzotriazole, benzodiazole,
- aromatic rings are pyridine, pyridazine, pyrimidine, pyrazine, thiophene, tetrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, imidazole, pyrazole, quinoline, triazole, isoquinoline, and indole, in particular pyridine, thiophene, imidazole, quinoline, isoquinoline, indole, and tetrazole.
- non-aromatic rings such as imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, and hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane, oxazetane, diazetane, and thiazetane.
- non-aromatic rings such as imidazolidine, piperazine, hexahydropyridazine, hexahydropyr
- non-aromatic rings are imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, azetidine, tropane, oxazinane
- oxazolane oxazepane
- thiazolane thiazinane
- thiazepane in particular imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, pyrrolidine, piperidine, azepane, oxazinane (morpholine), and thiazinane.
- the term “optionally substituted” is intended to mean that the group in question may be substituted one or several times, preferably 1-5 times, in particular 1-3 times) with group(s) selected from the same substituents as defined above for "optionally substituted aryl".
- certain compounds of the present invention are chiral. Moreover, the presence of certain cyclic fragments or multiple stereogenic atoms provides for the existence of diastereomeric forms of some of the compounds.
- the invention is intended to include all stereoisomers, including optical isomers, and mixtures thereof, as well as pure, partially enriched, or, where relevant, racemic forms.
- the / ⁇ -isomers are generally preferred.
- salts include acid addition salts and basic salts.
- acid addition salts are hydrochloride salts, fumarate, oxalate, etc.
- Examples of basic salts are salts where the (remaining) counter ion is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium salts, potassium salts, and ammonium ions ( + N(R') 4 ), where the R's independently designate optionally substituted d- 6 -alkyl, optionally substituted C 2 - 6 -alkenyl, optionally substituted aryl, or optionally substituted heteroaryl).
- alkali metals such as sodium and potassium
- alkaline earth metals such as calcium salts, potassium salts, and ammonium ions ( + N(R') 4 )
- R's independently designate optionally substituted d- 6 -alkyl, optionally substituted C 2 - 6 -alkenyl, optionally substituted aryl, or optionally substituted heteroaryl.
- Pharmaceutically acceptable salts are, e.g., those described in Remington's - The Science and Practice of Pharmacy,
- salt forming agents for application in the present invention are organic dicarboxylic acids such as oxalic, fumaric, and maleic acid, and the like.
- chalcones with amino groups can be prepared in their salt-forms thereby making the compounds particularly useful for pharmaceutical formulations.
- the use of appropriate selected salt form can be used to control the dissolution rate in vivo.
- the different salt forms have different bulk-properties which is of importance for the manufacturing process.
- amino-functional chalcones defined herein may be produced by methods known per se for the preparation of chalcones or methods which are analogous to such methods. Examples of excellent methods for preparing compounds of the l,3-bis-aromatic-prop-2- enone or the l,3-bis-aromatic-prop-2-ynone types are given in the following. Further examples of methods for the preparation of the compound used according to the present invention are described in WO 95/06628 and WO 93/17671 and in the references cited therein.
- aldehyde a benzaldehyde in the case where Ar 2 is phenyl
- Ar , Ar , X 1 , X , Y , Y , m, and p refer to the definitions given elsewhere herein.
- This reaction which is a condensation reaction, is suitably carried out under acid or base catalysed conditions.
- a review of such processes may be found in Nielsen, A ., Houlihahn, W ., Org. React. 16, 1968, p 1-444. In particular the method described by Wattanasin, S. and Murphy, S., Synthesis (1980) 647 has been found quite successful.
- the reaction may suitably be carried out in protic organic solvents, such as lower alcohols (e.g. methanol, ethanol, or tert-butanol), or lower carboxylic acids (formic, glacial acetic, or propionic acid), or in aprotic organic solvents such as ethers (e.g.
- the catalyst may be selected from sodium, lithium, potassium, barium, calcium, magnesium, aluminum, ammonium, or quaternary ammonium hydroxides, lower alkoxides (e.g.
- Primary aromatic amines such as aniline, free secondary amines such as dimethyl amine, diethyl amine, piperidine, or pyrrolidine as well as basic ion exchange resins may also be used.
- Acid catalysts may be selected from hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, sulfonic acids (such as paratoluenesulfonic or methanesulfonic acid), lower carboxylic acids (such as formic, acetic or propionic acid), lower halogenated carboxylic acids (such as trifluoroacetic acid), Lewis acids (such as BF 3 , POCI 3 , PCI 5 , or FeCI 3 ), or acid ion exchange resins.
- sulfonic acids such as paratoluenesulfonic or methanesulfonic acid
- lower carboxylic acids such as formic, acetic or propionic acid
- lower halogenated carboxylic acids such as trifluoroacetic acid
- Lewis acids such as BF 3 , POCI 3 , PCI 5 , or FeCI 3
- acid ion exchange resins such as BF 3 , POCI 3 , PCI 5 , or FeCI
- a drawback of the base catalysed condensation is the poor yield obtained if the aromatic ring in which the ketone or the aldehyde or both is substituted with one or more hydroxy groups.
- This drawback can be overcome by masking the phenolic group as described by T. Hidetsugu et al. in EP 0 370 461. Deprotection is easily performed by mineral acids such as hydrochloric acid.
- reaction is typically carried out at temperatures in the range of 0-100°C, e.g. at room temperature. Reaction times are typically from 30 m ⁇ n to 24 hours.
- the alkyl- or dialkyl aminomethyl-acetophenones and -benzaldehydes were prepared by reductive amination using substituted benzaldehyde, amine and sodium triacetoxyborohydride.
- the alkyl- or dialkyl aminoalkyl-acetophenones and -benzaldehydes were prepared from the corresponding bromo-compounds using halogen/metal exchange (n-BuLi) and quenching with N,N-dimethylacetamide and dimethylformamide, respectively.
- the activated derivative of the carboxylic acid may be an activated ester, an anhydride or, preferably, an acid halogenide, in particular the acid chloride.
- the reaction is normally carried out using the catalysts described by Tohda, Y. et al. cited above, namely copper(I)iodide/triphenylphosphine- palladium dichloride.
- the reaction is suitably carried out in triethylamine, a mixture of triethylamine and pyridine or triethylamine and toluene under a dry inert atmosphere such as nitrogen or argon.
- the reaction is generally carried out at reduced temperature such as in the range from -80°C to room temperature, the reaction time typically being from 30 minutes to 6 hours.
- the ethyne derivative may be prepared by standard methods, e.g. as described by Nielsen, S. F. Et al., Bioorg. Med. Chem. 6, pp 937-945 (1998).
- the carboxylic acids may likewise be prepared by standard procedures or by reductive amination as described in the examples.
- the present invention provides, in a further aspect, a compound (chalcone derivative) as defined herein for use as a drug substance, i. e. a medicament.
- the invention relates to the use of the compounds as defined herein for the preparation of a medicament for the treatment of infections, such as infections associated with bacteria, protozoas or Leishmania spp.
- the invention also provides in still further aspects a method for the treatment of infections such as bacteria, protozoas or Leishmania spp in a mammal comprising the administration of the compounds as defined herein to said mammal.
- the chalcone derivatives may be used for the treatment of bacterial infections in a mammal in need thereof.
- bacterial infection may be associated with common Gram-positive and/or Gram-negative pathogenes or with microaerophilic or anaerobic bacteria.
- antibiotic-sensitive or -resistant strains of S.aureus and/or E.faecium antibiotic-sensitive or -resistant strains of S.aureus and/or E.faecium.
- Other examples include community acquired and nosocomial respiratory infections, including S.pneumoniae, S.pyogenes and members of Enterobacteriaceae (e.g. E.coli), microaerophilic bacteria associated with gastric disease (e.g. Helicobacter pylori) or pathogenic anaerobic bacteria (e.g. Bacteroides fragilis and Clostridium species).
- the chalcone derivatives as provided herein can be used for the treatment of infections associated with protozoa in a mammal.
- infections are those caused by a protozoa selected from Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.
- the chalcone derivatives as defined herein can be used for the treatment of infections in a mammal associated with Leishmania spp. Such infections may be cutaneous and/or visceral.
- X 2 represents at least one substituent selected from d- 6 -alkyl, d_ 6 -alkoxy, d- 6 -alkylcarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylamino, optionally substituted heteroaryl, optionally substituted heteroarylamino, mono- and di(d- 6 " alkyl)amino, d-e-alkylcarbonylamino, optionally substituted d- 6 -alkylthio, optionally substituted heterocyclyl, optionally substituted heterocyclyloxy, optionally substituted heterocyclylamino and halogen, such as where X 2 represent the 2,4 or 2,5 substituents of a phenyl group as Ar 2 , appear to be particularly promising.
- X 2 represents one or more halogens located in the 2-, 3- and/or 4-position, especially in the 2- and/or 4-position, optionally in conjunction with an optionally substituted aryl or optionally substituted heteroaryl group in the 3- or 5-position are suitable in this aspect.
- X 2 represents at least one substituent selected from d- 6 -alkyl, d- 6 -alkoxy, d_ 5 -alkylcarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylamino, optionally substituted heteroaryl, optionally substituted heteroarylamino, optionally substituted (heteroarylalkyl)amino, optionally substituted (heteroarylalkyl)alkylamino, mono- and di(d.
- X 2 represent the 2,5 substituents of a phenyl group as Ar 2 , appear to be particularly promising.
- suitable embodiments are those in which X 1 is hydrogen, methoxy or hydroxy.
- X 2 represents one or two halogen atoms, such as chloro, located in the 2- and/or 4-positions.
- X 2 represents two substituents, located in the 2- and 5-positions, independently selected from alkoxy, alkyl, aryl, dialkylamino and pyridinylamino, with methoxy being a preferred alkoxy group.
- X 2 represents one substituent
- especially interesting compounds have X 2 located in the 3- or 4-position, and selected from mono- or di-alkylamino, pyridinylamino, imidazolyl and halogen, the latter being particularly suitable in the 4-position.
- Typical embodiments wherein X 2 represents three substituents are those wherein these substituents are located in the 2-, 4-, and 5- positions, such as 2-alkoxy, 4-alkoxy, hydroxy or halo, and 5-alkyl or aryl, as well as those wherein the three substituents are located in the 2-, 3-, and 5-positions, such as 2-alkoxy or alkyl, 3-alkoxy or alkyl, and 5-alkoxy or alkyl.
- preferred meanings of R are alkyl, especially methyl.
- embodiments wherein both m and p are 1 are suitable for treatment of infections associated with malaria.
- Such embodiments typically have Y 2 in the 2-, 3-, or 5- position.
- Embodiments in which m is 0 and p is 1 are currently interesting for the treatment of infections associated with malaria.
- Those typically have Y 2 in the 2-, 3-, or 4-position when Ar 2 is phenyl.
- Preferred such compounds are those where Y 2 is located at the 2-position, with further optional presence (X 2 ) of a 5-aryl substituent.
- typical meanings of X 1 in this context are 2- and/or 4-halo and 2- and/or 4-alkoxy, with 4-methoxy and 2- fluoro being preferred.
- Y 1 is the amino- substituent, in particular positioned in the 2, 3 or 4 position where Ar 1 is phenyl, are particularly promising for the treatment of infections caused by S. aureus.
- X 2 represents at least one substituent selected from d- 6 -alkyl, d- 6 -alkoxy, d- 6 - alkylcarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylamino, optionally substituted heteroaryl, optionally substituted heteroarylamino, mono- and di(C 1 .
- the chalcone derivatives are typically formulated in a pharmaceutical composition prior to use as a drug substance.
- the administration route of the compounds as defined herein may be any suitable route which leads to a concentration in the blood or tissue corresponding to a therapeutic effective concentration.
- the following administration routes may be applicable although the invention is not limited thereto: the oral route, the parenteral route, the cutaneous route, the nasal route, the rectal route, the vaginal route and the ocular route.
- the administration route is dependent on the particular compound in question, particularly, the choice of administration route depends on the physico-chemical properties of the compound together with the age and weight of the patient and on the particular disease or condition and the severity of the same.
- the compounds as defined herein may be contained in any appropriate amount in a pharmaceutical composition, and are generally contained in an amount of about 1-95% by weight of the total weight of the composition.
- the composition may be presented in a dosage form which is suitable for the oral, parenteral, rectal, cutaneous, nasal, vaginal and/or ocular administration route.
- the composition may be in form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, aerosols and in other suitable form.
- compositions may be formulated according to conventional pharmaceutical practice, see, e.g., "Remington's Pharmaceutical Sciences” and “Encyclopedia of Pharmaceutical Technology", edited by Swarbrick, 3. & 3. C. Boylan, Marcel Dekker, Inc., New York, 1988.
- the compounds defined herein are formulated with (at least) a pharmaceutically acceptable carrier or exipient.
- Pharmaceutically acceptable carriers or exipients are those known by the person skilled in the art.
- compositions according to the present invention provide in a further aspect a pharmaceutical composition
- a pharmaceutical composition comprising a compound as defined herein in combination with a pharmaceutically acceptable carrier.
- Pharmaceutical compositions according to the present invention may be formulated to release the active compound substantially immediately upon administration or at any substantially predetermined time or time period after administration.
- the latter type of compositions are generally known as controlled release formulations.
- controlled release formulation embraces i) formulations which create a substantially constant concentration of the drug within the body over an extended period of time, ii) formulations which after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time, iii) formulations which sustain drug action during a predetermined time period by maintaining a relatively, constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active drug substance (sawtooth kinetic pattern), iv) formulations which attempt to localize drug action by, e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ, v) formulations which attempt to target drug action by using carriers or chemical derivatives to deliver the drug to a particular target cell type.
- Controlled release formulations may also be denoted “sustained release”, “prolonged release”, “programmed release”, “time release”, “rate-controlled” and/or “targeted release” formulations.
- Controlled release pharmaceutical compositions may be presented in any suitable dosage forms, especially in dosage forms intended for oral, parenteral, cutaneous nasal, rectal, vaginal and/or ocular administration.
- suitable dosage forms especially in dosage forms intended for oral, parenteral, cutaneous nasal, rectal, vaginal and/or ocular administration.
- Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, liposomes, delivery devices such as those intended for oral, parenteral, cutaneous, nasal, vaginal or ocular use.
- compositions for oral use Preparation of solid dosage forms for oral use, controlled release oral dosage forms, fluid liquid compositions, parenteral compositions, controlled release parenteral compositions, rectal compositions, nasal compositions, percutaneous and topical compositions, controlled release percutaneous and topical compositions, and compositions for administration to the eye can be performed essentially as described in the applicant's earlier International application No. WO 99/00114, page 29, line 9, to page 40, line 3. Also, and more generally, the formulation and preparation of the above-mentioned compositions are well-known to those skilled in the art of pharmaceutical formulation. Specific formulations can be found in "Remington's Pharmaceutical Sciences".
- Dosages The compound are preferably administered in an amount of about 0.1-50 mg per kg body weight per day, such as about 0.5-25 mg per kg body weight per day.
- the dosage is normally 2 mg to 1 g per dose administered 1-4 times daily for 1 week to 12 months depending on the disease to be treated.
- the dosage for oral administration for the treatment of parasitic diseases is normally 1 mg to 1 g per dose administered 1-2 times daily for 1-4 weeks, in particular the treatment of malaria is to be continued for 1-2 weeks whereas the treatment of leishmaniasis will normally be carried out for 3-4 weeks.
- the dosage for oral administration for the treatment of bacterial diseases is normally 1 mg to 1 g per dose administered 1-4 times daily for 1 week to 12 months; in particular, the treatment of tuberculosis will normally be carried out for 6-12 months.
- the dosage for oral administration of the composition in order to prevent diseases is normally 1 mg to 75 mg per kg body weight per day.
- the dosage may be administered once or twice daily for a period starting 1 week before the exposure to the disease until 4 weeks after the exposure.
- compositions adapted for rectal use for preventing diseases a somewhat higher amount of the compound is usually preferred, i.e. from approximately 1 mg to 100 mg per kg body weight per day.
- a dose of about 0.1 mg to about 50 mg per kg body weight per day is convenient.
- a dose of about 0.1 mg to about 20 mg per kg body weight per day administered for 1 day to 3 months is convenient.
- intraarticular administration a dose of about 0.1 mg to about 20 mg per kg body weight per day is usually preferable.
- a solution in an aqueous medium of 0.5-2% or more of the active ingredients may be employed.
- a dose of about 1 mg to about 5 g administered 1- 10 times daily for 1 week to 12 months is usually preferable.
- the present invention also provides a method of predicting whether a chemical compound has a potential inhibitory effect against a microorganism selected from Helicobacter pylori and Plasmodium falciparum, said method comprising preparing a mixture of a dihydroorotate dehydrogenase, a substrate for dihydroorotate dehydrogenase and the chemcial compound, measuring the enzymatic activity of dihydroorotate dehydrogenase (A), comparing the enzymatic activity of dihydroorotate dehydrogenase (A) with the standard activity of dihydroorotate dehydrogenase (B) corresponding to the activity of a dihydroorotate dehydrogenase in a similar sample, but without the chemical compound, predicting that the chemical compound has a potential inhibitory effect against Helicobacter pylori and Plasmodium falciparum if A is significantly lower than B.
- the method can be performed as described under DHODH Assay in the Examples section. It should be noted that the method is not only applicable for the chalcone derivatives defined herein, but can be generally applied to predict the potential inhibitory effect of any compound. Preferably, however, the chemical compound is a chalcone derivative, e.g. a chalcone derivative as defined herein.
- the compounds were characterised by NMR (300 MHz) and GC-MS/LC-MS.
- 2-(2-Chloro-4-methoxy-phenyl)-2-methyl-propionitrile A solution of 2-(2-chloro-4-methoxy-phenyl)propionitrile (19 g, 0.097 mol) and methyliodide (7 mL, 0.11 mol) in dry DMF (100 mL) was flushed with argon for 2 min and cooled to 0°C. Sodium hydride (60% oil susp., 4.4 g, 0.11 mol) was added in small portions. The thick suspension was stirred for another 18h at 25°C and then poured into water (300 mL) and extracted with Et 2 0 (3 x 100 mL).
- 2-(5-Bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionitrile A solution of 2-(2-chloro-4-methoxy-phenyl)-2-methyl-propionitrile (17.5 g, 0.0835 mol) in TFA (100 mL) was cooled to 0°C. N-bromosuccinimide (14.9 g, 0.0835 mol) was added in small portions keeping the temperature below 5°C. The orange solution was stirred for 2h/25°C and evaporated to dryness. Water (200 mL) was added and the mixture was stirred vigorously for 1 h. The crude product was filtered off and recrystallized from boiling MeOH. The pure product was isolated as white needles.
- A020 (£)- 3-(2,4-Dichloro-phenyl)-l-(3-dimethylaminomethyl-phenyl)- propenone
- A022 (£)- 3-(2,4-Dichloro-phenyl)-l- ⁇ 3-[(3-dimethylamino-propylamino)- methyl]-phenyl ⁇ -propenone
- A042 (£)- 3-(2,4-Difluoro-phenyl)-l-(2-dimethylam ⁇ nomethyl-phenyl)- propenone
- A054 (£)- 3-(2,4-Dimethoxy-phenyl)-l-[2-(4-methyl-piperazin-l-ylmethyl)- phenyl]-propenone
- A081 (£)-3-(2 / 4-Dimethyl-phenyl)-l-[2-(4-methyl-piperazin-l-ylmethyl)- 10 phenyl]-propenone
- A083 (£)- 3-[4-Chloro-5-(l,l-dimethyl-allyl)-2-methoxy-phenyl]-l-[2-(4- methyl-piperaz ⁇ n-l-ylmethyl)-phenyl]-propenone
- A091 (£)- 3-(2-Dimethylaminomethyl-phenyl)-l-(3-dimethylaminomethyl- phenyl)-propenone
- AIOO (£)-l-(3-Dimethylaminomethyl-phenyl)-3-(4-methoxy-biphenyl-3-yl)- propenone
- Triethylsilane (0.150 mol) was added to a solution of 3-(2,4-Dichloro-phenyl)-l-(2- dimethylaminomethyl-phenyl)-propenone (0.0075 mol) in trifluoro acetic acid, stirred at 25 °C for 30 hours, before the solution was poured into ice-cold NaOH (2M, 150 mL). Extracted with EtOAc, dried over Na 2 S0 4 , filtered and evaporated on Celite®. Purified by flash chromatography (EtOAc/heptane, 3% Et 3 N).
- A104 (£ ) -3-[4-(2-Dimethylamino-ethyl)-phenyl]-l-(2-fluoro-4-methoxy- phenyl)-propenone
- A105 (f )-l-(4-Methoxy-phenyl)-3-(3-piperazin-l-ylmethyl-phenyl)-propenone Prepared by general procedure I using piperazine-1-carboxylic acid tert-butyl ester followed by deprotecton using trifluoroacetic acid in methylene chloride. The title compound was isolated as trifluoroacetate salt 43% yield (yellow crystals).
- A106 ⁇ £ -3-(3- ⁇ [(2-Methoxy-ethyl)-methyl-amino]-methyl ⁇ -phenyl)-l-(4- methoxy-phenyl)-propenone
- A112 (£ ) -3-[2-(2-Dimethylamino-ethyl)-phenyl]-l-(2-fluoro-4-methoxy- phenyl)-propenone
- A128 f£ -3-(3-Dibutylamino-phenyl)-l-(3-dimethylaminomethyI-4-hydroxy- phenyl)-propenone
- A135 f£ 3-(3,5-Di-tert-butyl-2-methoxy-phenyl)-l-(3-dimethylaminomethyl-4- hydroxy-phenyl)-propenone
- the fraction of compound metabolised during the 15 min of incubation was determined by comparison of blank and microsome-containing samples using a Waters Alliance 2690 separation module and Waters 996 PDA-detector(Waters. Milford, MA, USA.) Separation was performed on a XTerra MS C 18 column (150*2.1 mm I.D., 3,5 ⁇ m particle size) (Waters Milford, MA, USA) by.
- Initial conditions were 40% mobile phase A (acetonitrile) and 60% mobile phase B (10 mM ammonium acetate pH 9.5). During the first 20 minutes, the mobile phase was changed via a linear gradient to 90% A and 10% B. This was followed by a 5 minutes linear gradient to initial conditions, which were maintained for 5 min. The flow rate was 0.20 ml/min and injection volume 10 ⁇ l.
- Solubility of the compounds was determined by preparing a saturated solution of compound in 0.3 M phosphate buffer (pH 7.4 + 0.3) in a brown glass tube. The suspensions were rotated slowly for 24 hours. Aliquots were centrifuged for 10 minutes at 14.000 rpm and supernatants were diluted in 40% (v/v) acetonitrile in water prior to HPLC analysis. Concentrations of analytes were quantified against a standard curve and used as term of solubility.
- HPLC-UV method used for the assessment of solubility is the same as used in the in vitro metabolism assay.
- Evaluation of the pharmacokinetic properties of the compounds was done using female NMRI mice (weighing app. 30 g). Test articles were administrated intravenously and orally as a cassette dose formulations containing three compounds or as individual compounds. Samples of serum were taken at defined timepoints.
- proteins Prior to analysis, proteins were precipitated by deluding the samples (1 : 1) (v/v) with 100 % acetonitrile followed by centrifugation at 14.000 rpm in 10 min. The supernatant was used for the analysis.
- the screening assay was done in 200 ⁇ l MH-broth cultures in microtitre plates.
- MIC was determined in a microdilution assay using MH-broth as described by NCLLS (National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard - Fifth Edition. M7-A5 NCCLS 2000) modified to include uninoculated dilution series of test compounds to facilitate MIC determination if the test compound should precipitate.
- MIC was determined as the lowest concentration of test compound able to inhibit visible growth of bacteria.
- MICs for ATCC type strains fell within the limits posted by the NCCLS (National Committee for Clinical Laboratory Standards. Performance Stadards for Antimicrobial Susceptibility Testing; Eleventh Informational Supplement. M100-S11 NCCLS 2001) when tested against vancomycin, tetracycline, gentamycin.
- MIC and MBC of test compounds were determined in a broth macrodilution assay using 2 ml MH-broth cultures and an inoculum of approximately 5xl0E5 CFU/ml as described by Amsterdam (Amsterdam, D. Susceptibility testing of antimicrobials in liquid media. In V.Lorian (ed.): Antibiotics in Laboratory Median 4. edition. Williams & Wilkins 1996).
- MIC was determined as the minimal concentration of test compound able to inhibit visible growth of bacteria. Samples from cultures inhibited by test compound were plated onto unselective blood agar plates.
- MBC was determined as the minimal concentration of test compound able to decrease colony count on these plates below 0.1% compared to the original inoculum.
- test compounds with bactericidal activity is capable of decreasing surviving colony counts (CFU/ml) when incubated with bacteria.
- Bactericidal activity may be either primarily dependent on concentration of test compound or on incubation time with test compound.
- An example of a bactericidal compound (A031), which is primarily dependent on the concentration of the test compound is shown in Figure 3.
- An example of a bactericidal compound (A019) which is primarily dependent on the incubation time with the compound is shown in Figure 4.
- a WHO reference vaccine strain of L.major originally isolated from a patient in Iran were cultured in Medium 199 with Hanks ' Salts containing 0.02 mg/ml gentamycin, 25 mM HEPES, 4 mM L-glutamine, and 10% heat inactivated fetal calf serum (FCS). Incubation was carried out at 27°C. Promastigotes were harvested at day 3 of culture and used for the assay of inhibition of parasite growth.
- test compounds on promastigotes were assessed by a method modified from Pearson et al. Briefly, promastigotes (0.8xl0 6 /well) were incubated in 200 ⁇ l duplicate cultures either with a dilution series of test compound or medium alone in 96 wells flat buttom microtiter plates. After 2h of incubation, 1.5 ⁇ Ci of 3H-thymidine was added to each well and further incubated for 18 hours. The cultures were then harvested on Unifilter-GF/C microtiter filter plates (Packard Instruments), washed extensively and counted in a TopCount-NXT microplate scintillation counter (Packard Instruments).
- Plasmodium falciparum 3D7 was maintained in culture by a modification of the method originally described by Trager and Jensen.
- the parasites were grown in suspensions of human blood group 0 erythrocytes (RBC) maintained in RPMI1640 medium supplemented with 4.5 g/l Albumax II (Invitrogen), 10 mM hypoxantine, 1.4 mM L- glutamine and 0.05 mg/ml gentamicin. Cultures were incubated at 37°C in atmosphere of 92.5% nitrogen, 5.5% carbon dioxide, and 2% oxygen.
- erythrocytes infected with late developmental stages of malaria parasites are specifically retained within the column.
- the column was washed with PBS supplemented with 2% foetal calf serum and then the column was removed from the magnet and the retained late developmental stages of parasites were eluted and cultured for an additional 18 hours. At this time the culture is highly synchronous containing more than 90% ring stages.
- These synchronized cultures of ring stage parasites were used to assay for antimalarial parasites. Briefly, cultures of ring stage parasites were adjusted to 1% parasitemia by addition of uninfected RBC.
- DCIP-stock solution 40 mg DCIP and 10 ml 99 % Ethanol are mixed for 10 min at RT. Then 100 ⁇ l 1.0 M Tris-HCI pH 8 and miliQ H 2 0 are added to a final volume of 100 ml.
- the A 600 of the DCIP-stock solution are measured in a microtiter plate on the Powerwave x 340 (Bio-Tek instruments,Inc.)
- Dihydroorotate dehydrogenase (DHODH)-stock solution 25 mM dihydroorotate stock- solution is prepared by first dissolving in the same amount of mol NaOH and then miliQ H 2 0 is added to the final volume.
- Assay mix (10 ml solution): 600 ⁇ l of DHODH-stock solution and X ml (depending on the A 600 value of stock-solution) DCIP to a final A 600 2.5 are mixed. Then 0.1 M Tris-HCI pH 8.0 are added to a final volume of 10 ml.
- Licochalcone A (LicA) and 4'methoxy chalcone (4'MC) described in WO 93/17671 are used as reference compounds in the following discussion.
- Licochalcone A exhibit moderate bactericidal activity against common pathogenic Gram- positive non-fastidious bacteria including Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae.
- Licochalcone A maintains its activity also against antibiotic resistant bacteria, e.g. Staphylococcus aureus ATCC33591 (resistant to methicillin) and Enterococcus faecium #17051 (resistant to vancomycin).
- Staphylococcus aureus ATCC33591 resistant to methicillin
- Enterococcus faecium #17051 resistant to vancomycin
- Licochalcone A have only modest or no activity against the prototype pathogenic Gram-negative bacterium, Eschericia coli. 4'MC as a representative of non-hydroxyl chal
- aminochalcones retain the activity of Licochalcone A against pathogenic Gram-positive bacteria including antibiotic-resistant strains (cf. Table 1).
- Several aminochalcones exhibit increased potency against Gram- positive pathogens (e.g. A025, A030, A019, A033, A083).
- aminochalcones exhibit activity against Eschericia coli.
- aminochalcones e.g. A030, A031, A019, A083, A084
- exhibit considerable activity against the ESS strain of E.coli which generally is more susceptible to antibiotics than the type strain E.coli ATCC25922.
- several aminochalcones e.g.
- aminochalcones exhibit similar high activity against both Gram-positive bacteria and E.coli ESS and ATTC 25922 strains.
- aminochalcones can be modified to permeate and inhibit Gram-negative bacteria. This indicates the potential use of aminochalcones in the treatment of infections with Gram- negative bacteria.
- bactericidal action of a antibiotic is a necessity.
- aminochalcones retain the bactericidal action of Licochalcone A.
- the bactericidal action is predominantly dependent on the concentration of the compound (e.g. A031; cf. Figure 3); for others the bactericidal action is predominantly dependent on the time of incubation with the compound (e.g. A019; cf. Figure 4). This knowledge is helpful when designing dosing regimens for in vivo efficacy trials.
- Tabel 1 Comparasion of the effect of amino-chalcones and Licochalcone/4'MC on bacteria; MIC values in ⁇ M.
- A Staphylococcus aureus ATCC29213; B: Staphylococcus aureus ATCC33591 (resistant to methicillin); C: Staphylococcus intermedius #2357 (clinical isolate from the Copenhagen area); D: Enterococcus faecalis ATCC29212; E: Enterococcus faecium #17501 (vancomycin-resistant clinical isolate); F: Streptococcus pneumoniae #998 (clinical isolate); G: Eschericia coli ATCC25922 and H: Eschericia coli ESS. NA: no activity.
- Colonization of the gastric mucosa with Helicobacter pylori is an important pathogenic determinant for the development of gastritis and peptic ulcer.
- Aminochalcones exhibit activity against Helicobacter pylori.
- Several aminochalcones e.g. A026, A035, A037, A038, A045, A051, A063, A118, A124
- Metronidazol is an antibiotic commonly included in treatment regimens designed to eradicate Helicobacter colonization for the treatment of peptic ulcer.
- the activity of aminochalcones against both metronidazole-resistant and sensitive Helicobacter pylori clearly indicates the potential use of these compounds in the treatment of Helicobacter infections.
- Aminochalcones have been assayed in a single concentration of compound (100 ⁇ M) for activity against a panel of anaerobic bacteria containing common human pathogenic bacteria (Bacteroides fragilis, Clostridium perfringens, Clostridium difficele).
- Several aminochalcones e.g. AOll, A026, A034, A037, A038, A063, A090
- Plasmodium falciparum is a protozoan parasite transmitted by the mosquito, Anopheles, and causing malignant or severe malaria in humans.
- Licochalcone A exhibit activity against Plasmodium falciparum in vitro and protects mice from infection with P.yoelii and P. berghei (Chen et al., 1994).
- Aminochalcones exhibit activity in vitro against Plasmodium falciparum and several aminochalcones exhibit improved potency compared to Licochalcone A (cf. Table 2 and Figure 5). Futhermore the compounds are potent against chloroquine resistant parasites as shown in Table 3. The results clearly indicate the potential use of aminochalcones in the treatment of malaria.
- Table 2 Activity against Plasmodium falciparum 3D7.
- Leishamania major is a protozoan parasite transmitted by the sandfly, Phlebotomus, and causing cutaneous leishmaniasis or kala-azar in humans.
- Licochalcone A exhibit activity against Leishmania parasites and has shown efficacy in experimental animal models of cutaneous and visceral Leishmania infection (Chen et al., 1994).
- Aminochalcones exhibit activity in vitro against Leishamania major with significantly improved potency compared to Licochalcone A and 4'MC (cf. Table 4 and Figure 6). The results clearly indicate the potential use of aminochalcones in the treatment of Leishamania infection.
- amino-chalcones prepared are potent inhibitors of DHODH.
- the compounds are as potent as LicA and by far more potent than ordinary chalcones exemplified by 4'MC.
- aqueous solubility of the neutral chalcones described in WO 93/17671 is very low.
- a representative chalcone 4'-methoxy-chalcone has a solubility of ⁇ 0.05 mg/ml.
- a few chalcones have a higher solubility due to (metabolically unstable) hydroxyl groups in the molecule.
- LicA has a solubility of approximately 0.01 mg/ml.
- amino-chalcones described in this application are by far superior having solubility numbers in mg/ml (cf. Table 7).
- the bioavailability of the amino chalcones in mice is in general very high (e.g. 34% for A048).
- the mouse is a very fast metabolizer of the amino chalcones compared to rat and human (e.g. A102 mice: 28%; rat: 2%; human: in general lower than rat) the bioavailability in rat and man is expected to be even higher due to limited first pass metabolism.
- a number of amino-chalcones have significant effect in the in vivo models. As illiustrated on figure 7 and 8 the compounds cause a significant reduction of parasitaemia in plasmodium infedted mice, showing the potential of the compounds as drug candidates.
- the amino-chalcones in this application are expected to fulfill the criteria for a drug candidate.
- the metabolism is low, the solubility is high and the compounds are potent against parasites as well as (resistant) Gram positive and Gram negative bacteria.
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/514,625 US20060052600A1 (en) | 2002-05-17 | 2003-05-19 | Amino-functional chalcones |
EP03722316A EP1506157A2 (en) | 2002-05-17 | 2003-05-19 | Amino-functional chalcones |
AU2003229537A AU2003229537A1 (en) | 2002-05-17 | 2003-05-19 | Amino-functional chalcones |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA200200763 | 2002-05-17 | ||
DKPA200200763 | 2002-05-17 | ||
DKPA200200762 | 2002-05-17 | ||
DKPA200200762 | 2002-05-17 | ||
DKPA200201114 | 2002-07-18 | ||
DKPA200201114 | 2002-07-18 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003097575A2 true WO2003097575A2 (en) | 2003-11-27 |
WO2003097575A3 WO2003097575A3 (en) | 2004-02-26 |
Family
ID=29553776
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/DK2003/000331 WO2003097575A2 (en) | 2002-05-17 | 2003-05-19 | Amino-functional chalcones |
PCT/DK2003/000333 WO2003097576A2 (en) | 2002-05-17 | 2003-05-19 | Diamino-functional chalcones |
PCT/DK2003/000332 WO2003097574A2 (en) | 2002-05-17 | 2003-05-19 | Aminoalkoxy-functional chalcones |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/DK2003/000333 WO2003097576A2 (en) | 2002-05-17 | 2003-05-19 | Diamino-functional chalcones |
PCT/DK2003/000332 WO2003097574A2 (en) | 2002-05-17 | 2003-05-19 | Aminoalkoxy-functional chalcones |
Country Status (4)
Country | Link |
---|---|
US (3) | US7423181B2 (en) |
EP (3) | EP1506157A2 (en) |
AU (3) | AU2003229539A1 (en) |
WO (3) | WO2003097575A2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005042467A1 (en) * | 2003-10-31 | 2005-05-12 | Lica Pharmaceuticals A/S | Quaternary amino-functional chalcones |
CN105622492A (en) * | 2016-01-14 | 2016-06-01 | 郑州大学 | Chalcone derivatives with drug-resistant bacteria resistance activity |
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US20080221029A1 (en) * | 2002-10-31 | 2008-09-11 | Regents Of The University Of Colorado | Methods for treatment of thiol-containing compound deficient conditions |
US7399866B2 (en) | 2003-01-14 | 2008-07-15 | Cytokinetics, Inc. | Compounds, compositions, and methods |
JP4790704B2 (en) * | 2004-04-12 | 2011-10-12 | トレント・ファーマシューティカルズ・リミテッド | 2-propen-1-one as an HSP70 inducer |
US8110595B2 (en) | 2004-06-17 | 2012-02-07 | Cytokinetics, Inc. | Ureas and their use in the treatment of heart failure |
US7176222B2 (en) | 2004-07-27 | 2007-02-13 | Cytokinetics, Inc. | Syntheses of ureas |
US7538223B2 (en) | 2005-08-04 | 2009-05-26 | Cytokinetics, Inc. | Compounds, compositions and methods |
US7825120B2 (en) | 2005-12-15 | 2010-11-02 | Cytokinetics, Inc. | Certain substituted ((piperazin-1-ylmethyl)benzyl)ureas |
ES2419007T3 (en) | 2005-12-15 | 2013-08-19 | Cytokinetics, Inc. | Certain chemical entities, compositions and procedures |
US7718657B2 (en) | 2005-12-16 | 2010-05-18 | Cytokinetics, Inc. | Certain indanyl urea modulators of the cardiac sarcomere |
EP1962852B1 (en) | 2005-12-19 | 2017-01-25 | Cytokinetics, Inc. | Compounds, compositions and methods |
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WO2012150207A1 (en) | 2011-05-04 | 2012-11-08 | Bayer Cropscience Ag | Use of cyclopropanecarboxylic acid ester derivatives for controlling insecticide-resistant insects |
WO2012150206A2 (en) | 2011-05-04 | 2012-11-08 | Bayer Cropscience Ag | Novel cyclopropanoic acid ester derivatives as pest control agents |
US10071945B2 (en) | 2011-06-15 | 2018-09-11 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Nuclear receptor modulators and their use for the treatment and prevention of cancer |
CN105503788B (en) * | 2016-01-28 | 2017-11-07 | 中国人民解放军第二军医大学 | The substitution of one kind 3 the third 2 ketone compounds of alkene 1 and its application |
CN107235894B (en) * | 2017-06-21 | 2020-04-03 | 郑州大学 | Quaternary ammonium chalcone derivative with drug-resistant bacterium resisting activity, preparation method and application thereof |
US11325883B2 (en) | 2017-11-22 | 2022-05-10 | Temple University—Of the Commonwealth System of Higher Education | Functionalized N,N-dialkylamino phenyl ethers and their method of use |
CN110240549B (en) * | 2019-07-10 | 2022-01-07 | 南阳师范学院 | Amine alkoxy chalcone compound and preparation method and application thereof |
CN110272349B (en) * | 2019-07-10 | 2022-01-07 | 南阳师范学院 | 2' -hydroxy-3-phenyl propiophenone compound and preparation method and application thereof |
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WO1993017671A1 (en) * | 1992-03-06 | 1993-09-16 | Statens Seruminstitut | Treatment and prophylaxis of diseases caused by parasites, or bacteria |
WO1999000114A2 (en) * | 1997-06-26 | 1999-01-07 | Statens Serum Institut | Biologically active 1,3-bis-aromatic-prop-2-en-1-ones, 1,3-bis-aromatic-propan-1-ones, and 1,3-bis-aromatic-prop-2-yn-1-ones |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CS218450B1 (en) * | 1981-06-22 | 1983-02-25 | Alena Bradlerova | Azachalkons with basic group in the lateral chain and method of preparation thereof |
CS218446B3 (en) * | 1981-06-22 | 1983-02-25 | Alena Bradlerova | Azachalkons derived from the isovaniline derivative and method of preparation thereof |
US5523302A (en) * | 1993-11-24 | 1996-06-04 | The Du Pont Merck Pharmaceutical Company | Aromatic compounds containing basic and acidic termini useful as fibrinogen receptor antagonists |
-
2003
- 2003-05-19 WO PCT/DK2003/000331 patent/WO2003097575A2/en not_active Application Discontinuation
- 2003-05-19 WO PCT/DK2003/000333 patent/WO2003097576A2/en not_active Application Discontinuation
- 2003-05-19 EP EP03722316A patent/EP1506157A2/en not_active Withdrawn
- 2003-05-19 EP EP03722318A patent/EP1506158A2/en not_active Withdrawn
- 2003-05-19 US US10/514,829 patent/US7423181B2/en not_active Expired - Fee Related
- 2003-05-19 EP EP03722317A patent/EP1515940A2/en not_active Withdrawn
- 2003-05-19 WO PCT/DK2003/000332 patent/WO2003097574A2/en not_active Application Discontinuation
- 2003-05-19 US US10/514,821 patent/US7642367B2/en not_active Expired - Fee Related
- 2003-05-19 US US10/514,625 patent/US20060052600A1/en not_active Abandoned
- 2003-05-19 AU AU2003229539A patent/AU2003229539A1/en not_active Abandoned
- 2003-05-19 AU AU2003229538A patent/AU2003229538A1/en not_active Abandoned
- 2003-05-19 AU AU2003229537A patent/AU2003229537A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1993017671A1 (en) * | 1992-03-06 | 1993-09-16 | Statens Seruminstitut | Treatment and prophylaxis of diseases caused by parasites, or bacteria |
WO1999000114A2 (en) * | 1997-06-26 | 1999-01-07 | Statens Serum Institut | Biologically active 1,3-bis-aromatic-prop-2-en-1-ones, 1,3-bis-aromatic-propan-1-ones, and 1,3-bis-aromatic-prop-2-yn-1-ones |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005042467A1 (en) * | 2003-10-31 | 2005-05-12 | Lica Pharmaceuticals A/S | Quaternary amino-functional chalcones |
CN105622492A (en) * | 2016-01-14 | 2016-06-01 | 郑州大学 | Chalcone derivatives with drug-resistant bacteria resistance activity |
Also Published As
Publication number | Publication date |
---|---|
AU2003229539A1 (en) | 2003-12-02 |
US7423181B2 (en) | 2008-09-09 |
EP1506157A2 (en) | 2005-02-16 |
AU2003229537A1 (en) | 2003-12-02 |
US20060235073A1 (en) | 2006-10-19 |
WO2003097575A3 (en) | 2004-02-26 |
WO2003097574A2 (en) | 2003-11-27 |
EP1515940A2 (en) | 2005-03-23 |
AU2003229538A1 (en) | 2003-12-02 |
WO2003097576A2 (en) | 2003-11-27 |
AU2003229537A8 (en) | 2003-12-02 |
US20060052600A1 (en) | 2006-03-09 |
US20050227990A1 (en) | 2005-10-13 |
EP1506158A2 (en) | 2005-02-16 |
WO2003097574A3 (en) | 2004-02-26 |
US7642367B2 (en) | 2010-01-05 |
WO2003097576A3 (en) | 2004-03-18 |
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