EP1556007A2 - Composes tetracycline substituee servant au traitement du paludisme - Google Patents
Composes tetracycline substituee servant au traitement du paludismeInfo
- Publication number
- EP1556007A2 EP1556007A2 EP03781398A EP03781398A EP1556007A2 EP 1556007 A2 EP1556007 A2 EP 1556007A2 EP 03781398 A EP03781398 A EP 03781398A EP 03781398 A EP03781398 A EP 03781398A EP 1556007 A2 EP1556007 A2 EP 1556007A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- hydrogen
- substituted
- alkynyl
- alkenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- -1 tetracycline compounds Chemical class 0.000 title claims abstract description 254
- 239000004098 Tetracycline Substances 0.000 title claims abstract description 162
- 235000019364 tetracycline Nutrition 0.000 title claims abstract description 162
- 229960002180 tetracycline Drugs 0.000 title claims abstract description 153
- 229930101283 tetracycline Natural products 0.000 title claims abstract description 153
- 201000004792 malaria Diseases 0.000 title claims abstract description 125
- 238000000034 method Methods 0.000 claims abstract description 123
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- 230000000078 anti-malarial effect Effects 0.000 claims abstract description 22
- 239000003430 antimalarial agent Substances 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 239000003937 drug carrier Substances 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 118
- 125000000304 alkynyl group Chemical group 0.000 claims description 94
- 229910052739 hydrogen Inorganic materials 0.000 claims description 93
- 239000001257 hydrogen Substances 0.000 claims description 93
- 125000003342 alkenyl group Chemical group 0.000 claims description 88
- 125000003118 aryl group Chemical group 0.000 claims description 84
- 150000002431 hydrogen Chemical group 0.000 claims description 70
- 125000003545 alkoxy group Chemical group 0.000 claims description 64
- 125000003282 alkyl amino group Chemical group 0.000 claims description 59
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 59
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 51
- 125000004414 alkyl thio group Chemical group 0.000 claims description 51
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 48
- 229910052736 halogen Inorganic materials 0.000 claims description 48
- 150000002367 halogens Chemical class 0.000 claims description 47
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims description 40
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical class N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 150000003522 tetracyclines Chemical class 0.000 claims description 32
- 239000000651 prodrug Chemical group 0.000 claims description 30
- 229940002612 prodrug Drugs 0.000 claims description 30
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 22
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 229910052717 sulfur Chemical class 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 claims description 17
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 16
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 16
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 16
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims description 16
- 229960004023 minocycline Drugs 0.000 claims description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical class [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 229960003722 doxycycline Drugs 0.000 claims description 14
- 239000001301 oxygen Chemical class 0.000 claims description 14
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical class [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 239000011593 sulfur Chemical class 0.000 claims description 11
- 241000282414 Homo sapiens Species 0.000 claims description 9
- 230000000845 anti-microbial effect Effects 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 claims description 8
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 claims description 8
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 8
- YNWCUCSDUMVJKR-UHFFFAOYSA-N 4-[(7-chloroquinolin-4-yl)amino]-2-(pyrrolidin-1-ylmethyl)phenol Chemical compound OC1=CC=C(NC=2C3=CC=C(Cl)C=C3N=CC=2)C=C1CN1CCCC1 YNWCUCSDUMVJKR-UHFFFAOYSA-N 0.000 claims description 8
- LUBUTTBEBGYNJN-UHFFFAOYSA-N 4-amino-n-(5,6-dimethoxypyrimidin-4-yl)benzenesulfonamide;5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1.COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC LUBUTTBEBGYNJN-UHFFFAOYSA-N 0.000 claims description 8
- OVCDSSHSILBFBN-UHFFFAOYSA-N Amodiaquine Chemical compound C1=C(O)C(CN(CC)CC)=CC(NC=2C3=CC=C(Cl)C=C3N=CC=2)=C1 OVCDSSHSILBFBN-UHFFFAOYSA-N 0.000 claims description 8
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 8
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 claims description 8
- FOHHNHSLJDZUGQ-VWLOTQADSA-N Halofantrine Chemical compound FC(F)(F)C1=CC=C2C([C@@H](O)CCN(CCCC)CCCC)=CC3=C(Cl)C=C(Cl)C=C3C2=C1 FOHHNHSLJDZUGQ-VWLOTQADSA-N 0.000 claims description 8
- 239000004100 Oxytetracycline Substances 0.000 claims description 8
- 229960001444 amodiaquine Drugs 0.000 claims description 8
- 229950009959 amopyroquine Drugs 0.000 claims description 8
- 239000004599 antimicrobial Substances 0.000 claims description 8
- 125000003435 aroyl group Chemical group 0.000 claims description 8
- LRTRTVPZZJAADL-DAHZFVMQSA-N arteflene Chemical compound C(/[C@@]1(C)[C@@H]2C[C@H](OO1)[C@@H](C(C2)=O)C)=C/C1=CC=C(C(F)(F)F)C=C1C(F)(F)F LRTRTVPZZJAADL-DAHZFVMQSA-N 0.000 claims description 8
- 229950010777 arteflene Drugs 0.000 claims description 8
- 229960000981 artemether Drugs 0.000 claims description 8
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 claims description 8
- 229960004191 artemisinin Drugs 0.000 claims description 8
- 229930101531 artemisinin Natural products 0.000 claims description 8
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 claims description 8
- 229960004991 artesunate Drugs 0.000 claims description 8
- KUCQYCKVKVOKAY-CTYIDZIISA-N atovaquone Chemical compound C1([C@H]2CC[C@@H](CC2)C2=C(C(C3=CC=CC=C3C2=O)=O)O)=CC=C(Cl)C=C1 KUCQYCKVKVOKAY-CTYIDZIISA-N 0.000 claims description 8
- 229960003159 atovaquone Drugs 0.000 claims description 8
- 229960003677 chloroquine Drugs 0.000 claims description 8
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 8
- ISZNZKHCRKXXAU-UHFFFAOYSA-N chlorproguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C(Cl)=C1 ISZNZKHCRKXXAU-UHFFFAOYSA-N 0.000 claims description 8
- 229950000764 chlorproguanil Drugs 0.000 claims description 8
- 231100000135 cytotoxicity Toxicity 0.000 claims description 8
- 229960000860 dapsone Drugs 0.000 claims description 8
- 229960002398 demeclocycline Drugs 0.000 claims description 8
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 claims description 8
- 229960003242 halofantrine Drugs 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- DYLGFOYVTXJFJP-MYYYXRDXSA-N lumefantrine Chemical compound C12=CC(Cl)=CC=C2C=2C(C(O)CN(CCCC)CCCC)=CC(Cl)=CC=2\C1=C/C1=CC=C(Cl)C=C1 DYLGFOYVTXJFJP-MYYYXRDXSA-N 0.000 claims description 8
- 229960004985 lumefantrine Drugs 0.000 claims description 8
- 229960001962 mefloquine Drugs 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 229960000625 oxytetracycline Drugs 0.000 claims description 8
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 claims description 8
- 235000019366 oxytetracycline Nutrition 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 230000008092 positive effect Effects 0.000 claims description 8
- 229960005179 primaquine Drugs 0.000 claims description 8
- INDBQLZJXZLFIT-UHFFFAOYSA-N primaquine Chemical compound N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 INDBQLZJXZLFIT-UHFFFAOYSA-N 0.000 claims description 8
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 claims description 8
- 229960005385 proguanil Drugs 0.000 claims description 8
- 229950011262 pyronaridine Drugs 0.000 claims description 8
- 229960001404 quinidine Drugs 0.000 claims description 8
- 229960000948 quinine Drugs 0.000 claims description 8
- 150000003456 sulfonamides Chemical class 0.000 claims description 8
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 claims description 8
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 claims description 8
- 229960001082 trimethoprim Drugs 0.000 claims description 8
- 125000005907 alkyl ester group Chemical group 0.000 claims description 7
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 7
- 230000000844 anti-bacterial effect Effects 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 claims description 7
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 claims description 7
- 230000003013 cytotoxicity Effects 0.000 claims description 7
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 208000024891 symptom Diseases 0.000 claims description 7
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 6
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 206010019233 Headaches Diseases 0.000 claims description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- 206010041660 Splenomegaly Diseases 0.000 claims description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 208000007502 anemia Diseases 0.000 claims description 6
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 6
- 150000001721 carbon Chemical class 0.000 claims description 6
- 231100000869 headache Toxicity 0.000 claims description 6
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 6
- 206010025482 malaise Diseases 0.000 claims description 6
- 229910052705 radium Inorganic materials 0.000 claims description 6
- 229910052701 rubidium Inorganic materials 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 5
- 241000223960 Plasmodium falciparum Species 0.000 claims description 5
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 3
- PEPBFCOIJRULGJ-UHFFFAOYSA-N 3h-1,2,3-benzodioxazole Chemical compound C1=CC=C2NOOC2=C1 PEPBFCOIJRULGJ-UHFFFAOYSA-N 0.000 claims description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 3
- 241000224016 Plasmodium Species 0.000 claims description 3
- 241000223821 Plasmodium malariae Species 0.000 claims description 3
- 206010035501 Plasmodium malariae infection Diseases 0.000 claims description 3
- 241000223810 Plasmodium vivax Species 0.000 claims description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
- 206010037660 Pyrexia Diseases 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 3
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 claims description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 150000003536 tetrazoles Chemical class 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- 150000003852 triazoles Chemical class 0.000 claims description 3
- AEGIGNROXNVWPI-UHFFFAOYSA-N 1-[ethylperoxy(methoxy)methyl]peroxypropane Chemical group CCCOOC(OC)OOCC AEGIGNROXNVWPI-UHFFFAOYSA-N 0.000 claims description 2
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 2
- 241001505293 Plasmodium ovale Species 0.000 claims description 2
- 206010035502 Plasmodium ovale infection Diseases 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
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- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
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- MEGKRPMNPGTIIG-VNYBMUHKSA-N penimepicycline Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1.O=C([C@@]1(O)C(O)=C2[C@@H]([C@](C3=CC=CC(O)=C3C2=O)(C)O)C[C@H]1[C@@H](C=1O)N(C)C)C=1C(=O)NCN1CCN(CCO)CC1 MEGKRPMNPGTIIG-VNYBMUHKSA-N 0.000 description 1
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- 229950005777 penimocycline Drugs 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
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- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- XATZHCXBMKRRDO-REHNUXHNSA-N pipacycline Chemical compound O=C([C@@]1(O)C(O)=C2[C@@H]([C@](C3=CC=CC(O)=C3C2=O)(C)O)C[C@H]1[C@@H](C=1O)N(C)C)C=1C(=O)NCN1CCN(CCO)CC1 XATZHCXBMKRRDO-REHNUXHNSA-N 0.000 description 1
- 229950001465 pipacycline Drugs 0.000 description 1
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- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000005002 sporogony Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
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- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
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- 235000012222 talc Nutrition 0.000 description 1
- IFLREYGFSNHWGE-UHFFFAOYSA-N tetracene Chemical compound C1=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C21 IFLREYGFSNHWGE-UHFFFAOYSA-N 0.000 description 1
- 229940072172 tetracycline antibiotic Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005300 thiocarboxy group Chemical group C(=S)(O)* 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, ***e
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- R 4 is NR 4 R 4 , alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;
- R 3 , R 11 and R 12 are each hydrogen, or a pro-drug moiety;
- R 10 is hydrogen, a prodrug moiety, or linked to R 9 to form a ring;
- R 5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
- this invention also pertains to pharmaceutical compositions which include an effective amount of one of the above-described substituted tetracycline compounds and a pharmaceutically acceptable carrier
- This invention also features a packaged malarial treatment, including one or more of the substituted tetracycline compounds of the invention packaged with instructions for using the compound to treat malaria.
- this invention pertains to methods of treating or preventing malaria in a subject, by administering an effective amount of a substituted tetracycline compound.
- tetracycline compounds includes tetracycline family members such as methacycline, sancycline, apicycline, clomocycline, guamecycline, meglucycline, mepylcycline, penimepicycline, pipacycline, etamocycline, penimocycline, etc. as well as other tetracycline compounds having the characteristic naphthacene A-B-C-D ring structure. Additional tetracycline compounds can be found, for example, in U.S. Patent Application Serial No.: 09/234,847, and U.S. Patents Nos.
- tetracyclines regardless of specific formulation or chemical structure, were found to be highly effective pharmacologically against rickettsiae, a number of gram-positive and gram-negative bacteria, and the agents responsible for lymphogranuloma venereum, including conjunctivitis, and psittacosis.
- tetracyclines became known as "broad spectrum" antibiotics.
- the tetracyclines as a class rapidly became widely used for therapeutic purposes.
- the substituted tetracycline compound of the invention may have anti-microbial gram positive activity, as measured by assays known in the art or the assay described in Example 6.
- the anti-microbial gram positive activity of the substituted tetracycline compound is greater than about 0.0001 ⁇ g/ml, greater than about 0.05 ⁇ g/ml, greater than about 0.5 ⁇ g/ml, greater than about 1.0 ⁇ g/ml, or greater than about 5.0 ⁇ g/ml. Values and ranges included and/or intermediate of the values set forth herein are also intended to be within the scope of the present invention.
- the substituted tetracycline compound of the invention has a cytotoxicity which allows the compound to be administered in an effective amount to the subject with out causing prohibitive cytotoxic side effects.
- the cytotoxicity of the substituted tetracycline compound of the invention is greater than about 10 ⁇ g/ml, about 15 ⁇ g/ml, about 20 ⁇ g/ml, or about 25 ⁇ g/ml as measured by cytoxicity assays known in the art such as the assay described in Example 5.
- the substituted tetracycline compound of the invention has a MIC which allows it to perform its intended function, e.g., treat or prevent malaria in a subject.
- the MIC is a measure of the concentration of the compound necessary to inhibit the malaria parasite.
- the MIC can be tested using methods known in the art as well as the in vitro method described in Example 3 or the in vivo method described in Example 4.
- the MIC of a substituted tetracycline compound as measured in vivo is about 500 mg/kg or less, about 250 mg/kg or less, about 200 mg/kg or less, about 190 mg/kg or less, about 180 mg/kg or less, about 170 mg/kg or less, about 160 mg/kg or less, about 150 mg/kg or less, about 140 mg/kg or less, about 130 mg/kg or less, about 120 mg/kg or less, about 110 mg/kg or less, about 100 mg/kg or less, about 95 mg/kg or less, about 90 mg/kg or less, about 85 mg/kg or less, about 80 mg/kg or less, about 75 mg/kg or less, about 70 mg/kg or less, about 65 mg/kg or less, about 60 mg/kg or less, about 55 mg/kg or less, about 50 mg/kg or less, about 45 mg/kg or less, about 40 mg/kg or less, about 35 mg/kg or less, about 30 mg/kg or less, about 29 mg/kg or less, about 28 mg
- This invention provides a method for treating or preventing malaria in a subject by administering to the subject an effective amount of a substituted tetracycline compound, such that malaria is treated or prevented in said subject.
- X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O;
- R 2 , R 2 , R 4 , and R 4 are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;
- R 4 is NR 4 R 4 , alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;
- R 3 , R 1 ' and R 12 are each hydrogen, or a pro-drug moiety
- R 5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
- R 6 and R 6 are independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
- R 7 is hydrogen, alkylamino, dialkylamino, or a malaria interacting moiety;
- R 9 is hydrogen, or a malaria interacting moiety
- R is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
- Y' and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; with the proviso that the compound of formula I is not oxytetracycline, demeclocycline, doxycycline, chlorotetracycline, minocycline, or tetracycline; and pharmaceutically acceptable salts thereof.
- Examples of compounds of formula I which can be used in the methods of the invention include substituted tetracycline compounds wherein R , R , R , R , and R 12 are hydrogen; R 4 is NR R" and R 4' and R 4" are alkyl (e.g., methyl); and X is CR 6 R 6' .
- the substituted tetracycline compounds of the invention may also include substituted minocycline derivatives, e.g., wherein R , R , and R are hydrogen, and R is dialkylamino.
- the substituted tetracycline compound of the invention is substituted at the 7 or 9 position with a malaria interacting moiety.
- the term "malaria interacting moiety” is a moiety which allows the substituted tetracycline compound of the invention to perform its intended function, e.g., treat or prevent malaria. It may interact with the malaria parasite or allow other portions of the tetracycline molecule to interact with the parasite. It also may allow the molecule to treat malaria by affecting the way the tetracycline compound interacts with the malaria parasite, the subject, or other microbes.
- the malaria interacting moiety may alter the tetracycline compounds' properties such that the resulting compound is, for example, non- antibacterial.
- the malaria interacting moiety is a moiety which comprises from about 2 to 40, from about 3 to 30, from about 3 to 20 carbon, nitrogen, oxygen and sulfur atoms.
- the malaria interacting moiety may further be substituted with hydrogen and other substituents (e.g., halogens) which are not counted amongst the 2 to 40, from about 3 to 30, from about 3 to 20 atoms.
- the malaria interacting moiety comprises an aryl or heteroaryl moiety.
- the aryl or heteroaryl moiety can be substituted with any substituent which allows it to perform its intended function.
- Examples of malaria interacting moieties include aryl groups such as phenyl and heteroaryl groups (e.g., furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, and deazapurinyl).
- aryl groups such as phenyl and heteroaryl groups (e.g., furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinoliny
- the aryl group may be substituted or unsubstituted.
- substituents include, but are not limited, alkyl, alkenyl, alkynyl, aralkyl, alkoxyalkyl, aminoalkyl, amino, nitro, cyano, halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxy, thiol, formyl, acetyl, acyl, alkoxy (e.g., methylene dioxy, methoxy, ethoxy, propoxy, etc.) and heterocyclic (e.g., morpholino, piperazine, etc.).
- the substituents may be further substituted as appropriate.
- R a and R b are each independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, or heterocyclic (R a and R b may optionally be linked to form a ring); g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; n is O, 1, 2, or 3; and X a , X b , X c , X d , and X e are each independently optionally substituted carbon, oxygen, nitrogen, or sulfur. Furthermore, each carbon atom of the malaria interacting moieties shown above may be further substituted with substituents which allow the tetracycline compound to perform its intended function.
- substituents include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thio, amid
- the methods of the invention also include the use of substituted tetracycline compounds which are sancycline derivatives, e.g., wherein R 5 , R 6 , and R 6 are hydrogen.
- sancycline derivatives include tetracycline compounds wherein R 7 is a malaria interacting moiety.
- malaria interacting moieties which may be used for substituted sancycline compounds of the invention include those described above.
- other examples of malaria interacting moieties include, but are not limited to, aryl group such as substituted or unsubstituted phenyl or a heteroaryl moieties.
- substituted sancycline compounds include compounds wherein R 9 is hydrogen or a malaria interacting moiety.
- the substituted tetracycline compound has a molecular weight of less than 800, less than 600, less than 550, less than 500, or less than 400 grams/mole.
- alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
- a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 0 for straight chain, C 3 -C 6 for branched chain).
- cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
- C 2 -C 6 includes alkenyl groups containing 2 to 6 carbon atoms.
- alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
- alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
- lower alkyl as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure.
- Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
- COS-1 and CHO cell suspensions are prepared, seeded into 96-well tissue culture treated black-walled microtiter plates (density determined by cell line), and incubated overnight at 37°C, in 5% CO 2 and approximately 95% humidity. The following day serial dilutions of drug are prepared under sterile conditions and transferred to cell plates. Cell/Drug plates are incubated under the above conditions for 24 hours. Following the incubation period, media/drug is aspirated and 50 ⁇ l of Resazurin is added. Plates are then incubated under the above conditions for 2 hours and then in the dark at room temperature for an additional 30 minutes. Fluorescence measurements are taken (excitation 535 nm, emission 590 n ).
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Abstract
Priority Applications (1)
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EP10171327A EP2277504A1 (fr) | 2002-10-24 | 2003-10-24 | Composes tetracycline substituee servant au traitement du paludisme |
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US42125902P | 2002-10-24 | 2002-10-24 | |
US421259P | 2002-10-24 | ||
PCT/US2003/033927 WO2004038001A2 (fr) | 2002-10-24 | 2003-10-24 | Composes tetracycline substituee servant au traitement du paludisme |
Publications (2)
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EP1556007A2 true EP1556007A2 (fr) | 2005-07-27 |
EP1556007A4 EP1556007A4 (fr) | 2008-12-17 |
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EP10171327A Withdrawn EP2277504A1 (fr) | 2002-10-24 | 2003-10-24 | Composes tetracycline substituee servant au traitement du paludisme |
EP03781398A Withdrawn EP1556007A4 (fr) | 2002-10-24 | 2003-10-24 | Composes tetracycline substituee servant au traitement du paludisme |
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EP10171327A Withdrawn EP2277504A1 (fr) | 2002-10-24 | 2003-10-24 | Composes tetracycline substituee servant au traitement du paludisme |
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EP (2) | EP2277504A1 (fr) |
JP (2) | JP2006503898A (fr) |
AU (3) | AU2003287218C1 (fr) |
CA (1) | CA2502464A1 (fr) |
IL (1) | IL209319A0 (fr) |
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AU2002250331A1 (en) * | 2001-03-13 | 2002-09-24 | Paratek Pharmaceuticals, Inc. | 7-pyrollyl tetracycline compounds and methods of use thereof |
AU2003261161B2 (en) | 2002-07-12 | 2009-09-10 | Paratek Pharmaceuticals, Inc | 3, 10, and 12a substituted tetracycline compounds |
EP2319829A1 (fr) * | 2003-07-09 | 2011-05-11 | Paratek Pharmaceuticals, Inc. | Composés tétracyclines substitués em position 9 |
US20050137174A1 (en) * | 2003-07-09 | 2005-06-23 | Paratek Pharmaceuticals, Inc. | Prodrugs of 9-aminomethyl tetracycline compounds |
SI1753713T1 (sl) | 2004-05-21 | 2017-01-31 | President And Fellows Of Harvard College | Sinteza tetraciklinov in njihovih analogov |
EP2284151A3 (fr) * | 2004-10-25 | 2011-09-21 | Paratek Pharmaceuticals, Inc. | Composés de tétracycline substituée |
FR2891744B1 (fr) * | 2005-10-06 | 2009-10-09 | France Etat Armement | Application a la chimioprophylaxie du paludisme d'une association de chloroquine et de doxycycline |
WO2007117639A2 (fr) | 2006-04-07 | 2007-10-18 | The President And Fellows Of Harvard College | Synthèse de tétracyclines et d'analogues de celles-ci |
EP2479169B1 (fr) | 2006-10-11 | 2014-12-03 | President and Fellows of Harvard College | Synthèse d'un intermédiaire de l'énone |
BRPI0720569B8 (pt) * | 2006-12-21 | 2021-05-25 | Paratek Pharm Innc | compostos de tetraciclina substituída e uso dos ditos compostos para o tratamento de uma infecção bacteriana, viral ou parasitária |
JP2010525069A (ja) * | 2007-04-27 | 2010-07-22 | パラテック ファーマシューティカルズ インコーポレイテッド | アミノアルキルテトラサイクリン化合物の合成方法および精製方法 |
PT2271348T (pt) * | 2008-03-28 | 2018-04-16 | Paratek Pharm Innc | Formulação de comprimido oral de composto de tetraciclina |
SG10201806714PA (en) | 2008-08-08 | 2018-09-27 | Tetraphase Pharmaceuticals Inc | C7-fluoro substituted tetracycline compounds |
US9073829B2 (en) | 2009-04-30 | 2015-07-07 | President And Fellows Of Harvard College | Synthesis of tetracyclines and intermediates thereto |
CA2761241C (fr) | 2009-05-08 | 2018-02-27 | Tetraphase Pharmaceuticals, Inc. | Composes de tetracycline |
CA2772386C (fr) | 2009-08-28 | 2017-09-19 | Tetraphase Pharmaceuticals, Inc. | Composes tetracycline |
CN101967108B (zh) * | 2010-09-13 | 2013-06-19 | 苏春华 | 一种美他环素的衍生物 |
JP5792902B2 (ja) * | 2011-07-26 | 2015-10-14 | 山東亨利醫藥科技有限責任公司 | 9−アミノメチルで置換されたテトラサイクリン系化合物 |
BR112015004523B1 (pt) | 2012-08-31 | 2020-08-04 | Tetraphase Pharmaceuticals, Inc | Compostos de tetraciclina, composições farmacêuticas e seus usos |
MX2015011760A (es) | 2013-03-15 | 2016-06-10 | Melinta Therapeutics Inc | Metodos para tratar infecciones en pacientes obesos y con sobrepeso usando antibioticos. |
SG11201903327PA (en) | 2016-10-19 | 2019-05-30 | Tetraphase Pharmaceuticals Inc | Crystalline forms of eravacycline |
CA3095102A1 (fr) * | 2018-04-06 | 2019-10-10 | Paratek Pharmaceuticals, Inc. | Procede de preparation de chlorhydrate de sarecycline |
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- 2003-10-24 EP EP03781398A patent/EP1556007A4/fr not_active Withdrawn
- 2003-10-24 WO PCT/US2003/033927 patent/WO2004038001A2/fr active Application Filing
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- 2003-10-24 JP JP2004547165A patent/JP2006503898A/ja active Pending
-
2010
- 2010-03-16 AU AU2010200973A patent/AU2010200973A1/en not_active Abandoned
- 2010-03-16 AU AU2010200971A patent/AU2010200971A1/en not_active Abandoned
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Publication number | Publication date |
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WO2004038001A3 (fr) | 2004-11-11 |
WO2004038001A2 (fr) | 2004-05-06 |
EP1556007A4 (fr) | 2008-12-17 |
AU2010200973A1 (en) | 2010-04-01 |
EP2277504A1 (fr) | 2011-01-26 |
IL209319A0 (en) | 2011-01-31 |
AU2010200971A1 (en) | 2010-04-01 |
JP2006503898A (ja) | 2006-02-02 |
AU2003287218C1 (en) | 2010-07-15 |
AU2003287218A1 (en) | 2004-05-13 |
JP2011037890A (ja) | 2011-02-24 |
CA2502464A1 (fr) | 2004-05-06 |
AU2003287218B2 (en) | 2009-12-17 |
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