CA1174603A - Method of inhibiting the growth of protozoa - Google Patents
Method of inhibiting the growth of protozoaInfo
- Publication number
- CA1174603A CA1174603A CA000379588A CA379588A CA1174603A CA 1174603 A CA1174603 A CA 1174603A CA 000379588 A CA000379588 A CA 000379588A CA 379588 A CA379588 A CA 379588A CA 1174603 A CA1174603 A CA 1174603A
- Authority
- CA
- Canada
- Prior art keywords
- acid
- group
- alpha
- amino acid
- compounds
- 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.)
- Expired
Links
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 15
- 230000012010 growth Effects 0.000 title abstract description 21
- 238000000034 method Methods 0.000 title abstract description 18
- 241001465754 Metazoa Species 0.000 claims abstract description 30
- 150000001412 amines Chemical class 0.000 claims abstract description 22
- -1 procarbozine Chemical compound 0.000 claims description 73
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 claims description 45
- 238000011282 treatment Methods 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 150000001413 amino acids Chemical class 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 13
- 108010006654 Bleomycin Proteins 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 229960001561 bleomycin Drugs 0.000 claims description 10
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 10
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 9
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 9
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 206010037075 Protozoal infections Diseases 0.000 claims description 7
- 150000002431 hydrogen Chemical group 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 7
- 229940127089 cytotoxic agent Drugs 0.000 claims description 6
- KRUVSRGJKCHYMY-UHFFFAOYSA-N 1,3-bis(3-carbamimidoylphenyl)urea Chemical compound NC(=N)C1=CC=CC(NC(=O)NC=2C=C(C=CC=2)C(N)=N)=C1 KRUVSRGJKCHYMY-UHFFFAOYSA-N 0.000 claims description 5
- WZIPHSLUGLMTRU-UHFFFAOYSA-N 6-n-(2-amino-1,6-dimethylpyrimidin-1-ium-4-yl)-1,2-dimethylquinolin-1-ium-4,6-diamine;methyl sulfate Chemical compound COS(O)(=O)=O.COS([O-])(=O)=O.C=1C=C2N(C)C(C)=CC(=N)C2=CC=1NC1=CC(C)=[N+](C)C(N)=N1 WZIPHSLUGLMTRU-UHFFFAOYSA-N 0.000 claims description 5
- 229950007857 amicarbalide Drugs 0.000 claims description 5
- 229960003683 amprolium Drugs 0.000 claims description 5
- 239000003904 antiprotozoal agent Substances 0.000 claims description 5
- 239000002254 cytotoxic agent Substances 0.000 claims description 5
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 5
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 5
- PJBQYZZKGNOKNJ-UHFFFAOYSA-M hydron;5-[(2-methylpyridin-1-ium-1-yl)methyl]-2-propylpyrimidin-4-amine;dichloride Chemical compound Cl.[Cl-].NC1=NC(CCC)=NC=C1C[N+]1=CC=CC=C1C PJBQYZZKGNOKNJ-UHFFFAOYSA-M 0.000 claims description 5
- 238000011321 prophylaxis Methods 0.000 claims description 5
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 4
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 claims description 4
- 229960002227 clindamycin Drugs 0.000 claims description 4
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 4
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 claims description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 4
- KMJWBVJQFGRCEB-UHFFFAOYSA-O 4-n-(4-imino-1,2-dimethylquinolin-6-yl)-1,6-dimethylpyrimidin-1-ium-2,4-diamine Chemical compound C=1C=C2N(C)C(C)=CC(=N)C2=CC=1NC1=CC(C)=[N+](C)C(N)=N1 KMJWBVJQFGRCEB-UHFFFAOYSA-O 0.000 claims description 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 3
- MOOFYEJFXBSZGE-QJUDHZBZSA-N 1,2-bis[(z)-(4-chlorophenyl)methylideneamino]guanidine Chemical compound C=1C=C(Cl)C=CC=1\C=N/N=C(/N)N\N=C/C1=CC=C(Cl)C=C1 MOOFYEJFXBSZGE-QJUDHZBZSA-N 0.000 claims description 2
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 claims description 2
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 claims description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 2
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 claims description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 2
- 102100021906 Cyclin-O Human genes 0.000 claims description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 2
- 101000897441 Homo sapiens Cyclin-O Proteins 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- UKHWDRMMMYWSFL-UHFFFAOYSA-N Nicarbazin Chemical compound CC=1C=C(C)NC(=O)N=1.C1=CC([N+](=O)[O-])=CC=C1NC(=O)NC1=CC=C([N+]([O-])=O)C=C1 UKHWDRMMMYWSFL-UHFFFAOYSA-N 0.000 claims description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 2
- 229940009456 adriamycin Drugs 0.000 claims description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims description 2
- 229960003942 amphotericin b Drugs 0.000 claims description 2
- 229960002756 azacitidine Drugs 0.000 claims description 2
- 229950003639 buquinolate Drugs 0.000 claims description 2
- 229960002092 busulfan Drugs 0.000 claims description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 2
- 229960004630 chlorambucil Drugs 0.000 claims description 2
- 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 2
- 229960004397 cyclophosphamide Drugs 0.000 claims description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 2
- 229960000975 daunorubicin Drugs 0.000 claims description 2
- LVVXOXRUTDAKFE-UHFFFAOYSA-N ethyl 6,7-bis(2-methylpropoxy)-4-oxo-1h-quinoline-3-carboxylate Chemical compound CC(C)COC1=C(OCC(C)C)C=C2C(=O)C(C(=O)OCC)=CNC2=C1 LVVXOXRUTDAKFE-UHFFFAOYSA-N 0.000 claims description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 2
- 229960002949 fluorouracil Drugs 0.000 claims description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 2
- 229960004961 mechlorethamine Drugs 0.000 claims description 2
- 229960001428 mercaptopurine Drugs 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 229960004023 minocycline Drugs 0.000 claims description 2
- 229940073485 nicarbazin Drugs 0.000 claims description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 2
- 229960004618 prednisone Drugs 0.000 claims description 2
- 229960005179 primaquine Drugs 0.000 claims description 2
- 229960000948 quinine Drugs 0.000 claims description 2
- 229960004591 robenidine Drugs 0.000 claims description 2
- 229960001196 thiotepa Drugs 0.000 claims description 2
- 229960003087 tioguanine Drugs 0.000 claims description 2
- 229950000574 tryparsamide Drugs 0.000 claims description 2
- 229960003048 vinblastine Drugs 0.000 claims description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 2
- 229960004528 vincristine Drugs 0.000 claims description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 2
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 claims description 2
- 229960004355 vindesine Drugs 0.000 claims description 2
- 229940000425 combination drug Drugs 0.000 claims 3
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 claims 3
- 229960004448 pentamidine Drugs 0.000 claims 3
- XNYZHCFCZNMTFY-UHFFFAOYSA-N diminazene Chemical compound C1=CC(C(=N)N)=CC=C1N\N=N\C1=CC=C(C(N)=N)C=C1 XNYZHCFCZNMTFY-UHFFFAOYSA-N 0.000 claims 2
- 229930191564 Monensin Natural products 0.000 claims 1
- GAOZTHIDHYLHMS-UHFFFAOYSA-N Monensin A Natural products O1C(CC)(C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CCC1C(O1)(C)CCC21CC(O)C(C)C(C(C)C(OC)C(C)C(O)=O)O2 GAOZTHIDHYLHMS-UHFFFAOYSA-N 0.000 claims 1
- 229950007095 diminazene Drugs 0.000 claims 1
- 229960005358 monensin Drugs 0.000 claims 1
- GAOZTHIDHYLHMS-KEOBGNEYSA-N monensin A Chemical compound C([C@@](O1)(C)[C@H]2CC[C@@](O2)(CC)[C@H]2[C@H](C[C@@H](O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C[C@@]21C[C@H](O)[C@@H](C)[C@@H]([C@@H](C)[C@@H](OC)[C@H](C)C(O)=O)O2 GAOZTHIDHYLHMS-KEOBGNEYSA-N 0.000 claims 1
- INDBQLZJXZLFIT-UHFFFAOYSA-N primaquine Chemical compound N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 INDBQLZJXZLFIT-UHFFFAOYSA-N 0.000 claims 1
- UULSDCUWMKTMND-UHFFFAOYSA-N tryparsamide Chemical compound NC(=O)CNC1=CC=C([As](O)(O)=O)C=C1 UULSDCUWMKTMND-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 98
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 80
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 52
- 125000001309 chloro group Chemical group Cl* 0.000 description 41
- 239000000243 solution Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 34
- 239000002253 acid Substances 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 241000287828 Gallus gallus Species 0.000 description 22
- 235000013330 chicken meat Nutrition 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 208000015181 infectious disease Diseases 0.000 description 21
- 229940024606 amino acid Drugs 0.000 description 20
- 239000003651 drinking water Substances 0.000 description 20
- 235000020188 drinking water Nutrition 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- 239000003153 chemical reaction reagent Substances 0.000 description 18
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 230000000875 corresponding effect Effects 0.000 description 17
- 229960004132 diethyl ether Drugs 0.000 description 17
- 235000019441 ethanol Nutrition 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- 241000223932 Eimeria tenella Species 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 230000002152 alkylating effect Effects 0.000 description 12
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 12
- 230000003902 lesion Effects 0.000 description 12
- 229920000768 polyamine Polymers 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- 239000000010 aprotic solvent Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 229960004756 ethanol Drugs 0.000 description 10
- 230000007062 hydrolysis Effects 0.000 description 10
- 238000006460 hydrolysis reaction Methods 0.000 description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical class NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 10
- 229940086542 triethylamine Drugs 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000005700 Putrescine Substances 0.000 description 9
- 229960001701 chloroform Drugs 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 150000004820 halides Chemical class 0.000 description 9
- 244000144977 poultry Species 0.000 description 9
- 235000013594 poultry meat Nutrition 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 208000003495 Coccidiosis Diseases 0.000 description 8
- 206010023076 Isosporiasis Diseases 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 229940073584 methylene chloride Drugs 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 241000271566 Aves Species 0.000 description 7
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 7
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 7
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 229960003104 ornithine Drugs 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 241000224483 Coccidia Species 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000011260 aqueous acid Substances 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 6
- 229960003390 magnesium sulfate Drugs 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 241000894007 species Species 0.000 description 6
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 241000223105 Trypanosoma brucei Species 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 150000004985 diamines Chemical class 0.000 description 5
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 5
- OKQSSSVVBOUMNZ-UHFFFAOYSA-N diminazene diaceturate Chemical compound CC(=O)NCC(O)=O.CC(=O)NCC(O)=O.C1=CC(C(=N)N)=CC=C1NN=NC1=CC=C(C(N)=N)C=C1 OKQSSSVVBOUMNZ-UHFFFAOYSA-N 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical group 0.000 description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 description 5
- 229960004592 isopropanol Drugs 0.000 description 5
- ARNWQMJQALNBBV-UHFFFAOYSA-N lithium carbide Chemical compound [Li+].[Li+].[C-]#[C-] ARNWQMJQALNBBV-UHFFFAOYSA-N 0.000 description 5
- 235000010755 mineral Nutrition 0.000 description 5
- 239000011707 mineral Substances 0.000 description 5
- 210000003250 oocyst Anatomy 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000000069 prophylactic effect Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- 208000000230 African Trypanosomiasis Diseases 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 4
- XXTZHYXQVWRADW-UHFFFAOYSA-N diazomethanone Chemical class [N]N=C=O XXTZHYXQVWRADW-UHFFFAOYSA-N 0.000 description 4
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 4
- 229940113088 dimethylacetamide Drugs 0.000 description 4
- 239000002532 enzyme inhibitor Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 229940052303 ethers for general anesthesia Drugs 0.000 description 4
- CHDFNIZLAAFFPX-UHFFFAOYSA-N ethoxyethane;oxolane Chemical compound CCOCC.C1CCOC1 CHDFNIZLAAFFPX-UHFFFAOYSA-N 0.000 description 4
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 150000003951 lactams Chemical class 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 4
- 229940067157 phenylhydrazine Drugs 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 4
- 229940063673 spermidine Drugs 0.000 description 4
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 4
- FJJYHTVHBVXEEQ-UHFFFAOYSA-N 2,2-dimethylpropanal Chemical compound CC(C)(C)C=O FJJYHTVHBVXEEQ-UHFFFAOYSA-N 0.000 description 3
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241001375804 Mastigophora Species 0.000 description 3
- 102000052812 Ornithine decarboxylases Human genes 0.000 description 3
- 108700005126 Ornithine decarboxylases Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 3
- 241000223104 Trypanosoma Species 0.000 description 3
- 241000224557 Trypanosoma brucei brucei Species 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 229960003121 arginine Drugs 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000032823 cell division Effects 0.000 description 3
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 238000006114 decarboxylation reaction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 231100000676 disease causative agent Toxicity 0.000 description 3
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 230000002427 irreversible effect Effects 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 244000045947 parasite Species 0.000 description 3
- 230000003071 parasitic effect Effects 0.000 description 3
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 3
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229940063675 spermine Drugs 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- QAPXLUZMMFIIBI-UHFFFAOYSA-N 1,1,3,3-tetrafluoropropan-2-one Chemical class FC(F)C(=O)C(F)F QAPXLUZMMFIIBI-UHFFFAOYSA-N 0.000 description 2
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 2
- BVNYROHOUZCIEL-UHFFFAOYSA-N 2,2-diethylbutanal Chemical compound CCC(CC)(CC)C=O BVNYROHOUZCIEL-UHFFFAOYSA-N 0.000 description 2
- MUXPPYATEKVUBJ-UHFFFAOYSA-N 2,2-diethylbutanoyl chloride Chemical compound CCC(CC)(CC)C(Cl)=O MUXPPYATEKVUBJ-UHFFFAOYSA-N 0.000 description 2
- DNLPDGCZFXNNQO-UHFFFAOYSA-N 2-(5-fluoro-4-oxopentyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCC(=O)CF)C(=O)C2=C1 DNLPDGCZFXNNQO-UHFFFAOYSA-N 0.000 description 2
- KTZQXOLUWRTUAY-UHFFFAOYSA-N 2-(6-fluoro-5-oxohexan-2-yl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(C(CCC(=O)CF)C)C(=O)C2=C1 KTZQXOLUWRTUAY-UHFFFAOYSA-N 0.000 description 2
- JYVLIDXNZAXMDK-UHFFFAOYSA-N 2-pentanol Substances CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 2
- YGMQDBCXHASOHO-UHFFFAOYSA-N 3-bromopropan-1-amine;hydrochloride Chemical compound Cl.NCCCBr YGMQDBCXHASOHO-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 241000389783 Bulbonaricus brucei Species 0.000 description 2
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical compound CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 2
- 241000252983 Caecum Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 102000004031 Carboxy-Lyases Human genes 0.000 description 2
- 108090000489 Carboxy-Lyases Proteins 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 241000223924 Eimeria Species 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 241000606766 Haemophilus parainfluenzae Species 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 description 2
- 229910018540 Si C Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229960001570 ademetionine Drugs 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000003972 antineoplastic antibiotic Substances 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 description 2
- GRCDJFHYVYUNHM-UHFFFAOYSA-N bromodifluoromethane Chemical compound FC(F)Br GRCDJFHYVYUNHM-UHFFFAOYSA-N 0.000 description 2
- VHRGRCVQAFMJIZ-UHFFFAOYSA-N cadaverine Chemical compound NCCCCCN VHRGRCVQAFMJIZ-UHFFFAOYSA-N 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 210000004534 cecum Anatomy 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 229940106265 charcoal Drugs 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- 239000003224 coccidiostatic agent Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 239000003954 decarboxylase inhibitor Substances 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 244000144992 flock Species 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000008241 heterogeneous mixture Substances 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 229960003646 lysine Drugs 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 210000003936 merozoite Anatomy 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- CEOCUCXOSQUXGV-UHFFFAOYSA-N methanidylphosphanium Chemical class [PH3]=C CEOCUCXOSQUXGV-UHFFFAOYSA-N 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 235000006109 methionine Nutrition 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- MBXNQZHITVCSLJ-UHFFFAOYSA-N methyl fluorosulfonate Chemical compound COS(F)(=O)=O MBXNQZHITVCSLJ-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- WSGCRAOTEDLMFQ-UHFFFAOYSA-N nonan-5-one Chemical compound CCCCC(=O)CCCC WSGCRAOTEDLMFQ-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N ortho-diethylbenzene Natural products CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- YBVNFKZSMZGRAD-UHFFFAOYSA-N pentamidine isethionate Chemical compound OCCS(O)(=O)=O.OCCS(O)(=O)=O.C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 YBVNFKZSMZGRAD-UHFFFAOYSA-N 0.000 description 2
- 229960001624 pentamidine isethionate Drugs 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- AFDMODCXODAXLC-UHFFFAOYSA-N phenylmethanimine Chemical compound N=CC1=CC=CC=C1 AFDMODCXODAXLC-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 2
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 2
- 125000006308 propyl amino group Chemical group 0.000 description 2
- 208000028172 protozoa infectious disease Diseases 0.000 description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910010271 silicon carbide Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- 201000002311 trypanosomiasis Diseases 0.000 description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- DAJKXFBCODIPEX-UHFFFAOYSA-N 1,1,1-trifluorohexane-2,5-diamine Chemical compound CC(N)CCC(N)C(F)(F)F DAJKXFBCODIPEX-UHFFFAOYSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- HKIPCXRNASWFRU-UHFFFAOYSA-N 1,3-difluoropropan-2-one Chemical class FCC(=O)CF HKIPCXRNASWFRU-UHFFFAOYSA-N 0.000 description 1
- VHBWTTKVMJEUQA-UHFFFAOYSA-M 1,3-dithiolan-2-ylidene(methyl)sulfanium;iodide Chemical compound [I-].CSC1=[S+]CCS1 VHBWTTKVMJEUQA-UHFFFAOYSA-M 0.000 description 1
- XCWPBWWTGHQKDR-UHFFFAOYSA-N 1,3-dithiolane-2-thione Chemical compound S=C1SCCS1 XCWPBWWTGHQKDR-UHFFFAOYSA-N 0.000 description 1
- NWBCRWCKZUXDNV-UHFFFAOYSA-N 1-(ethylsulfinylmethylsulfanyl)ethane Chemical compound CCSCS(=O)CC NWBCRWCKZUXDNV-UHFFFAOYSA-N 0.000 description 1
- YSUINMDKTTYCFN-UHFFFAOYSA-N 1-fluorohexane-2,5-diamine Chemical compound CC(N)CCC(N)CF YSUINMDKTTYCFN-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- VOLJNJRRHNKYBB-UHFFFAOYSA-N 2,5-diamino-2-(difluoromethyl)hexanoic acid Chemical compound CC(N)CCC(N)(C(F)F)C(O)=O VOLJNJRRHNKYBB-UHFFFAOYSA-N 0.000 description 1
- SMKZHIMEFTXNNG-UHFFFAOYSA-N 2,5-diamino-2-(difluoromethyl)pent-3-enoic acid Chemical compound NCC=CC(N)(C(F)F)C(O)=O SMKZHIMEFTXNNG-UHFFFAOYSA-N 0.000 description 1
- RSHAFLMQMASOCX-UHFFFAOYSA-N 2,5-diamino-2-(fluoromethyl)hexanoic acid Chemical compound CC(N)CCC(N)(CF)C(O)=O RSHAFLMQMASOCX-UHFFFAOYSA-N 0.000 description 1
- VZKIJNFPNWRGLM-UHFFFAOYSA-N 2,5-diamino-2-(fluoromethyl)pent-3-enoic acid Chemical compound NCC=CC(N)(CF)C(O)=O VZKIJNFPNWRGLM-UHFFFAOYSA-N 0.000 description 1
- PYSFCFGTQFSVRE-UHFFFAOYSA-N 2,5-diamino-2-(fluoromethyl)pentanoic acid Chemical compound NCCCC(N)(CF)C(O)=O PYSFCFGTQFSVRE-UHFFFAOYSA-N 0.000 description 1
- GFBGNMMWPGUBFE-UHFFFAOYSA-N 2,5-diamino-2-(trifluoromethyl)hexanoic acid Chemical compound CC(N)CCC(N)(C(O)=O)C(F)(F)F GFBGNMMWPGUBFE-UHFFFAOYSA-N 0.000 description 1
- KCACQHUQULACFM-UHFFFAOYSA-N 2,5-diamino-2-(trifluoromethyl)pent-3-enoic acid Chemical compound NCC=CC(N)(C(O)=O)C(F)(F)F KCACQHUQULACFM-UHFFFAOYSA-N 0.000 description 1
- AUJCZWDHZDJWQH-UHFFFAOYSA-N 2,5-diamino-2-(trifluoromethyl)pentanoic acid Chemical compound NCCCC(N)(C(O)=O)C(F)(F)F AUJCZWDHZDJWQH-UHFFFAOYSA-N 0.000 description 1
- DOMOITJRCPARQV-UHFFFAOYSA-N 2,5-diamino-2-ethynylhexanoic acid Chemical compound CC(N)CCC(N)(C#C)C(O)=O DOMOITJRCPARQV-UHFFFAOYSA-N 0.000 description 1
- RELZRRUTLXPXNC-UHFFFAOYSA-N 2,5-diamino-2-ethynylpent-3-enoic acid Chemical compound NCC=CC(N)(C#C)C(O)=O RELZRRUTLXPXNC-UHFFFAOYSA-N 0.000 description 1
- JWWZUFCRQMJENK-UHFFFAOYSA-N 2,5-diamino-2-ethynylpentanoic acid Chemical compound NCCCC(N)(C#C)C(O)=O JWWZUFCRQMJENK-UHFFFAOYSA-N 0.000 description 1
- LNDPCYHWPSQBCA-UHFFFAOYSA-N 2,5-diamino-2-methylpentanoic acid Chemical compound OC(=O)C(N)(C)CCCN LNDPCYHWPSQBCA-UHFFFAOYSA-N 0.000 description 1
- NAQXSFUEPDPFNI-UHFFFAOYSA-N 2-(4-hydroxypentyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCC(O)C)C(=O)C2=C1 NAQXSFUEPDPFNI-UHFFFAOYSA-N 0.000 description 1
- UQATVDBDMOBBBN-UHFFFAOYSA-N 2-(6-fluoro-6-hydroxyhexan-2-yl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(C(CCCC(O)F)C)C(=O)C2=C1 UQATVDBDMOBBBN-UHFFFAOYSA-N 0.000 description 1
- FRRAALIYWQYLHM-UHFFFAOYSA-N 2-(difluoromethyl)pentane-1,4-diamine Chemical compound CC(N)CC(CN)C(F)F FRRAALIYWQYLHM-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- QHOINBKBMJLHPY-UHFFFAOYSA-N 2-chloroethyl formate Chemical compound ClCCOC=O QHOINBKBMJLHPY-UHFFFAOYSA-N 0.000 description 1
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 1
- BSMGLVDZZMBWQB-UHFFFAOYSA-N 2-methyl-1-phenylpropan-1-one Chemical compound CC(C)C(=O)C1=CC=CC=C1 BSMGLVDZZMBWQB-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- ZTGQZSKPSJUEBU-UHFFFAOYSA-N 3-bromopropan-1-amine Chemical compound NCCCBr ZTGQZSKPSJUEBU-UHFFFAOYSA-N 0.000 description 1
- AEDORKVKMIVLBW-BLDDREHASA-N 3-oxo-3-[[(2r,3s,4s,5r,6r)-3,4,5-trihydroxy-6-[[5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl]methoxy]oxan-2-yl]methoxy]propanoic acid Chemical compound OCC1=C(O)C(C)=NC=C1CO[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](COC(=O)CC(O)=O)O1 AEDORKVKMIVLBW-BLDDREHASA-N 0.000 description 1
- STXHPGKNMJVJKL-UHFFFAOYSA-N 4-(1,3-dioxoisoindol-2-yl)butanoyl chloride Chemical compound C1=CC=C2C(=O)N(CCCC(=O)Cl)C(=O)C2=C1 STXHPGKNMJVJKL-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- JEQGEEHYAFQUBH-UHFFFAOYSA-N 4-bromobutan-1-amine;hydrochloride Chemical compound Cl.NCCCCBr JEQGEEHYAFQUBH-UHFFFAOYSA-N 0.000 description 1
- DUNYJJMVWIDOPH-UHFFFAOYSA-N 4-bromobutan-2-amine;hydrobromide Chemical compound Br.CC(N)CCBr DUNYJJMVWIDOPH-UHFFFAOYSA-N 0.000 description 1
- GJOHLWZHWQUKAU-UHFFFAOYSA-N 5-azaniumylpentan-2-yl-(6-methoxyquinolin-8-yl)azanium;dihydrogen phosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 GJOHLWZHWQUKAU-UHFFFAOYSA-N 0.000 description 1
- PKOKVLWYGQNQDJ-UHFFFAOYSA-N 5-fluoropentane-1,4-diamine;dihydrochloride Chemical compound Cl.Cl.NCCCC(N)CF PKOKVLWYGQNQDJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 102000005758 Adenosylmethionine decarboxylase Human genes 0.000 description 1
- 108010070753 Adenosylmethionine decarboxylase Proteins 0.000 description 1
- QYPPJABKJHAVHS-UHFFFAOYSA-N Agmatine Natural products NCCCCNC(N)=N QYPPJABKJHAVHS-UHFFFAOYSA-N 0.000 description 1
- 206010001935 American trypanosomiasis Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000272517 Anseriformes Species 0.000 description 1
- 102000004452 Arginase Human genes 0.000 description 1
- 108700024123 Arginases Proteins 0.000 description 1
- 208000003723 Bovine Trypanosomiasis Diseases 0.000 description 1
- IJKGDPVFYVXHEG-UHFFFAOYSA-N CCCCCC1C=CC(Br)=CC1=N Chemical compound CCCCCC1C=CC(Br)=CC1=N IJKGDPVFYVXHEG-UHFFFAOYSA-N 0.000 description 1
- FAPWYRCQGJNNSJ-UHFFFAOYSA-L Calcium DL-pantothenate Chemical compound [Ca+2].OCC(C)(C)C(O)C(=O)NCCC([O-])=O.OCC(C)(C)C(O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UHFFFAOYSA-L 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 208000024699 Chagas disease Diseases 0.000 description 1
- XWCDCDSDNJVCLO-UHFFFAOYSA-N Chlorofluoromethane Chemical compound FCCl XWCDCDSDNJVCLO-UHFFFAOYSA-N 0.000 description 1
- 235000019743 Choline chloride Nutrition 0.000 description 1
- 241000193455 Clostridium cadaveris Species 0.000 description 1
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- 239000004470 DL Methionine Substances 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241001379910 Ephemera danica Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 241000224466 Giardia Species 0.000 description 1
- 241001502121 Glossina brevipalpis Species 0.000 description 1
- 241000948219 Histomonas Species 0.000 description 1
- 241001507061 Isopora Species 0.000 description 1
- 240000007049 Juglans regia Species 0.000 description 1
- 235000009496 Juglans regia Nutrition 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 150000000996 L-ascorbic acids Chemical class 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 241000222722 Leishmania <genus> Species 0.000 description 1
- 208000004554 Leishmaniasis Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 240000004658 Medicago sativa Species 0.000 description 1
- 235000017587 Medicago sativa ssp. sativa Nutrition 0.000 description 1
- 102000007357 Methionine adenosyltransferase Human genes 0.000 description 1
- 108010007784 Methionine adenosyltransferase Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 1
- 241000287530 Psittaciformes Species 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000287231 Serinus Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000223996 Toxoplasma Species 0.000 description 1
- 241000224526 Trichomonas Species 0.000 description 1
- 241001442399 Trypanosoma brucei gambiense Species 0.000 description 1
- 241001442397 Trypanosoma brucei rhodesiense Species 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- 241000223091 Trypanosoma lewisi Species 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 235000019740 Vitamins/micromineral premix Nutrition 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- QYPPJABKJHAVHS-UHFFFAOYSA-P agmatinium(2+) Chemical compound NC(=[NH2+])NCCCC[NH3+] QYPPJABKJHAVHS-UHFFFAOYSA-P 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000000842 anti-protozoal effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- ODJWWYHANGMPBK-UHFFFAOYSA-N azido 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)ON=[N+]=[N-] ODJWWYHANGMPBK-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-M benzenecarboximidate Chemical compound [NH-]C(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-M 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- FMWLUWPQPKEARP-UHFFFAOYSA-N bromodichloromethane Chemical compound ClC(Cl)Br FMWLUWPQPKEARP-UHFFFAOYSA-N 0.000 description 1
- LHMHCLYDBQOYTO-UHFFFAOYSA-N bromofluoromethane Chemical compound FCBr LHMHCLYDBQOYTO-UHFFFAOYSA-N 0.000 description 1
- RJCQBQGAPKAMLL-UHFFFAOYSA-N bromotrifluoromethane Chemical compound FC(F)(F)Br RJCQBQGAPKAMLL-UHFFFAOYSA-N 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 1
- CHHJDCVKYCVTHD-UHFFFAOYSA-N chloromethyl formate Chemical compound ClCOC=O CHHJDCVKYCVTHD-UHFFFAOYSA-N 0.000 description 1
- AFYPFACVUDMOHA-UHFFFAOYSA-N chlorotrifluoromethane Chemical compound FC(F)(F)Cl AFYPFACVUDMOHA-UHFFFAOYSA-N 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 description 1
- 229960003178 choline chloride Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 229940116318 copper carbonate Drugs 0.000 description 1
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- CGZZMOTZOONQIA-UHFFFAOYSA-N cycloheptanone Chemical compound O=C1CCCCCC1 CGZZMOTZOONQIA-UHFFFAOYSA-N 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- PBGGNZZGJIKBMJ-UHFFFAOYSA-N di(propan-2-yl)azanide Chemical compound CC(C)[N-]C(C)C PBGGNZZGJIKBMJ-UHFFFAOYSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- HNLZCOJXSLDGKD-UHFFFAOYSA-N dichloro(iodo)methane Chemical compound ClC(Cl)I HNLZCOJXSLDGKD-UHFFFAOYSA-N 0.000 description 1
- YSLFMGDEEXOKHF-UHFFFAOYSA-N difluoro(iodo)methane Chemical compound FC(F)I YSLFMGDEEXOKHF-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- CGINSMZJABBSAK-UHFFFAOYSA-N dimethylborinothioic acid Chemical compound CB(C)S CGINSMZJABBSAK-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- FJPAMFNRCFEGSD-UHFFFAOYSA-N eflornithine hydrochloride monohydrate Chemical compound O.Cl.NCCCC(N)(C(F)F)C(O)=O FJPAMFNRCFEGSD-UHFFFAOYSA-N 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- XGVXNTVBGYLJIR-UHFFFAOYSA-N fluoroiodomethane Chemical compound FCI XGVXNTVBGYLJIR-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- QIADQCOYEFCREQ-UHFFFAOYSA-N hept-6-yne-2,5-diamine Chemical compound CC(N)CCC(N)C#C QIADQCOYEFCREQ-UHFFFAOYSA-N 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 208000029080 human African trypanosomiasis Diseases 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 108700016226 indium-bleomycin Proteins 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 229940099596 manganese sulfate Drugs 0.000 description 1
- 239000011702 manganese sulphate Substances 0.000 description 1
- 235000007079 manganese sulphate Nutrition 0.000 description 1
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N methionine Chemical compound CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 150000002741 methionine derivatives Chemical class 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 1
- 206010034754 petechiae Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- PJGSXYOJTGTZAV-UHFFFAOYSA-N pinacolone Chemical compound CC(=O)C(C)(C)C PJGSXYOJTGTZAV-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000063 preceeding effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000008262 pumice Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229940096017 silver fluoride Drugs 0.000 description 1
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 description 1
- 201000002612 sleeping sickness Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- UEYIAABRKWHXJV-UHFFFAOYSA-M sodium;2-(4-arsonoanilino)ethanimidate Chemical compound [Na+].NC(=O)CNC1=CC=C([As](O)([O-])=O)C=C1 UEYIAABRKWHXJV-UHFFFAOYSA-M 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002311 subsequent effect Effects 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 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 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CULOEOTWMUCRSJ-UHFFFAOYSA-M thallium(i) fluoride Chemical compound [Tl]F CULOEOTWMUCRSJ-UHFFFAOYSA-M 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 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
- VPAYJEUHKVESSD-UHFFFAOYSA-N trifluoroiodomethane Chemical compound FC(F)(F)I VPAYJEUHKVESSD-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-O triphenylphosphanium Chemical compound C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-O 0.000 description 1
- 210000003812 trophozoite Anatomy 0.000 description 1
- 208000037972 tropical disease Diseases 0.000 description 1
- 230000000654 trypanocidal effect Effects 0.000 description 1
- XKGLSKVNOSHTAD-UHFFFAOYSA-N valerophenone Chemical compound CCCCC(=O)C1=CC=CC=C1 XKGLSKVNOSHTAD-UHFFFAOYSA-N 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/105—Aliphatic or alicyclic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/116—Heterocyclic compounds
- A23K20/132—Heterocyclic compounds containing only one nitrogen as hetero atom
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Polymers & Plastics (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Food Science & Technology (AREA)
- Animal Husbandry (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Tropical Medicine & Parasitology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Feed For Specific Animals (AREA)
- Fodder In General (AREA)
Abstract
M-1076-Cl METHOD OF INHIBITING THE GROWTH
OF PROTOZOA
ABSTRACT
a-Substituted amines and .alpha.-substituted-.alpha.-amino acids are described which are useful in inhibiting the growth of protozoa in animals.
OF PROTOZOA
ABSTRACT
a-Substituted amines and .alpha.-substituted-.alpha.-amino acids are described which are useful in inhibiting the growth of protozoa in animals.
Description
M--1076--Cl ,t 1~4~33 METHOD OF I2aHIBITING THE t;ROWTH
Technical Fie_d This invention relates to certain ~-substituted amines and ~-substituted-amino acids which are useful in inhibiting the growth of protozoa in animals and particularly in poultry.
Background Art Polyamines have been implicated in many aspects of cell division. Impairment of the biosynthesis of poly-amines by means of enzyme inhibitors is believed to cause a decrease in cell proliferation in mammals. Although the physiological role of polyamines has not been clearly delineated, there is evidence to suggest their involvement with cell division and growth, H.G. Williams-Ashman et al., The Italian J. Biochem. 25, 5-32 (1976), !~
~ 3 M-1076-C1 A. Raina and J. Janne, Med. Biol. 53, 121-147 (1975) and D.H. Russell, Life Sciences 13, 1635-1647 (1973).
Polyamines are also known to be essential growth factors for certain microorganisms, as for example E.
coli, Enterobacter, Klebsiella, Staphylococcus aureus, C. cadaveris, Salmonella typhosa and Haemophilus parainfluenza. There is evidence to suggest that poly-amines are associated with both normal and neoplastic mammalian cell growth, there being an increase in both the synthesis and accumulation of polyamines following a stimulus causing cellular proliferation. It is also known that there is a correlation between polyamine formation and the activity of the decarboxylase enzymes of ornithine, S-adenosylmethionine, arginine and lysine.
The term polyamine is taken to include the diamine putrescine and the polyamines spermidine and spermine.
Putrescine is the decarboxylation product of ornithine, catalyzed by ornithine decarboxylase. Putrescine forma-tion may also occur by decarboxylation of arginine to form agmatine, which is hydrolyzed to give putrescine and urea. Arginine is also involved in ornithine formation by action of the enzyme arginase. Activation of methio-nine by the enzyme S-adenosylmethionine synthetase forms S-adenosylmethionine which is decarboxylated. The propylamine moiety of the activated methionine may then be transferred to putrescine to form spermidine. Alter-natively, the propylamine moiety may be transferred to spermidine to form spermine. Hence, putrescine serves as a precursor to spermidine and spermine. Additionally, putrescine has been shown to have a marked regulatory effect upon the polyamine biosynthetic pathway. Also an increased synthesis of putrescine has been shown to be an early indication that a tissue will undergo renewed growth processes. Cadaverine, which is the decarboxyl-ation product of lysine, has been shown to stimulate theactivity of S-adenosylmethionine decarboxylase and is known to be essential to the growth processes of many 117~
microorganisms, for example, H. parainfluenza.
The rationale of polyamine metabolism has been suggested by Cohen, Science 205, 964 (1979). The apparent unique role of polyamine metabolism in trysano-somes and the dependence of trysanosomes upon ornithinedecarboxylase as a source of putrescine further supports our observations that certain specific ornithine de-carboxylase inhibitors of polyamine synthesis are highly effective in inhibiting the growth of protozoa.
SUMMARY OF THE INVENTION
We have discovered that certain compounds that belong to a class of irreversible inhibitors of ornithine de-carboxylase are useful in inhibiting the growth of protozoa.
Moreover, this inhibition occurs throughout a wide spectrum of protozoa such as with members of the subphylum Sarcomastigophora and Sporozoa. More particularly, the class of compounds hereinafter described are particularly useful in inhibiting the growth of members of the super-class of Mastigophora, specifically Trypanosoma brucei brucei and members of the class of Telosporea, specifically Eimeria tenella the organism which causes cocidiosis in poultry.
The compounds useful in the practice of this invention are a-substituted amines or a-substituted-a-amino acids having the general formula y Z-C-R
(I) wherein Rl is hydrogen or carboxy; Y is selected from the group consisting of CH2F, CHF2, CF3 and C-CH; 2 is , - M-1076-Cl ~7~ ;3 selected from the group consisting of H2N-~CH2)3, H2N-CH-(CH2)~ and H2N-CH2CH=CH; with the proviso that when Rl is hydrogen, Y cannot be CF3 and Z must be H2N-CH-(CH2)2; and the salts and individual optical isomers thereof.
When administered 1n vivo to animals containing active protozoal infections, the compounds of formula (I) can be utilized to treat such animals by inhibiting the further growth of the protozoal infections. Alternatively, the compounds described above can be administered prophylactically to prevent such protozoal infections from occurring.
DETAILED DESCRIPTION OF THE INVENTION
In general formula (I) above the symbol Rl is represented either by hydrogen or a carboxyl group. Where the symbol Rl is hydrogen a class of a-substituted amines is delineated. Where the symbol Rl is the carboxyl group, a class of ~-substituted-~-amino acids is delineated.
The symbol Y represents either an acetylenic group or a fluoro-substituted methyl group. The fluoro-substi-tuted methyl groups are illustrated by the monofluoro-methyl, difluoromethyl or trifluoromethyl radicals.
The symbol Z represents either the 3-aminopropyl group, the 3-amino-3-methylpropyl group or the 3-amino-1-propylene group. The saturated groups, viz. the 3-amino-propyl group and the 3-amino-3-methylpropyl group represent the preferred side chains.
M-1076-Cl ~L7~6~3 The proviso limitation is intended to exclude certain classes of diamines from the scope of compounds encom-passing this invention. Excluded from the invention via this proviso limitation are ~-substituted diamines where-in the symbol Z is the 3-aminopropyl group or the 3-amino-l-propylene group, i.e., those compounds having the general formulae y H2N- (CH2) 3-CH-NH2 (II) and y H2N-CH2CH=cH-cH-NH2 (III) wherein the symbol Y is as previously defined.
Specifically excluded from the remaining ~-substituted diamines is the species wherein the symbol Y represents the trifluoromethyl group. Thus, compound (IV), 4-methyl-1-trifluoromethyl-1,4-butanediamine, is specifically excluded from the scope of compounds which can be usefully employed.
C,F3 H2N-C,H- (CH2) 2-CH-NH2 (IV) Included within the scope of compounds that can be employed are ~-substituted amino acids having the formula:
:, Y, H2N-(CH2)3-C-COOH
(V) M-1076-Cl ~17.~ 3 H2N--CH- (CH2) 2-C--COOH
CH3 ~H2 (VI) and y H2N-CH2CH=CH-C-COOH
(VII) In formulae (V), (VI) and (VII) above, the symbol Y is as previously defined.
The ~-substituted amines included within the scope of compounds that can be usefully employed in the practice of this invention are defined by the general formula y H2N-CH- (CH2) 2-CH--NH2 (VIII) wherein the symbol Y represents the CH2F, CHF2 and C--CH
groups, but in the case of the diamines exludes the CF3 group.
Illustrative examples of the salts of the compounds of this invention include non-toxic acid addition salts formed with inorganic acids, such as, hydrochloric, hydrobromic, sulfuric and phosphoric acid, and organic acids, such as, methanesulfonic, salicyclic, maleic, malonic, tartaric, citric, cyclamic and ascorbic acids.
~7~3 M-1076-cl A preferred class of compounds of this invention are those compounds in which the symbol Y represents the difluoromethyl group. Another preferred class of com-pounds is delineated where the symbol Z represents the 3-aminopropyl moiety or the 3-amino-3-methylpropyl moiety.
In addition to the salts indicated above, the term salts is taken to include those internal salts or zwitter-ions of those compounds of formula (I) above that are amphoteric in nature. Moreover, whereas the optical configuration for the compounds described herein is not specifically designated, it is recognized that the ~-carbon atom possesses an asymmetric center and that individual optical isomers of these compounds exist. Accordingly, both the d- and l-optical isomers as well as the racemic mixtures are contemplated as being within the scope of this invention Lactam formation can occur where the symbol Rl represents the carboxyl group and the symbol Z represents the 3-aminopropyl moiety or the 3-amino-3-methylpropyl moiety as represented by the following general formula I
Y - C -- C = O
(CH2)3 NH
(IX) In the above general formula the symbol Y is as originally described. Where the symbol Z represents the 3-amino-3-methylpropyl moiety, the (CH2)3 group in formula (IX) above can be additionally substituted with a 3-methyl group.
~Lf.7a~3 M-1076-Cl Illustrative examples of compounds useful in accordance with the teachings of this invention include:
Technical Fie_d This invention relates to certain ~-substituted amines and ~-substituted-amino acids which are useful in inhibiting the growth of protozoa in animals and particularly in poultry.
Background Art Polyamines have been implicated in many aspects of cell division. Impairment of the biosynthesis of poly-amines by means of enzyme inhibitors is believed to cause a decrease in cell proliferation in mammals. Although the physiological role of polyamines has not been clearly delineated, there is evidence to suggest their involvement with cell division and growth, H.G. Williams-Ashman et al., The Italian J. Biochem. 25, 5-32 (1976), !~
~ 3 M-1076-C1 A. Raina and J. Janne, Med. Biol. 53, 121-147 (1975) and D.H. Russell, Life Sciences 13, 1635-1647 (1973).
Polyamines are also known to be essential growth factors for certain microorganisms, as for example E.
coli, Enterobacter, Klebsiella, Staphylococcus aureus, C. cadaveris, Salmonella typhosa and Haemophilus parainfluenza. There is evidence to suggest that poly-amines are associated with both normal and neoplastic mammalian cell growth, there being an increase in both the synthesis and accumulation of polyamines following a stimulus causing cellular proliferation. It is also known that there is a correlation between polyamine formation and the activity of the decarboxylase enzymes of ornithine, S-adenosylmethionine, arginine and lysine.
The term polyamine is taken to include the diamine putrescine and the polyamines spermidine and spermine.
Putrescine is the decarboxylation product of ornithine, catalyzed by ornithine decarboxylase. Putrescine forma-tion may also occur by decarboxylation of arginine to form agmatine, which is hydrolyzed to give putrescine and urea. Arginine is also involved in ornithine formation by action of the enzyme arginase. Activation of methio-nine by the enzyme S-adenosylmethionine synthetase forms S-adenosylmethionine which is decarboxylated. The propylamine moiety of the activated methionine may then be transferred to putrescine to form spermidine. Alter-natively, the propylamine moiety may be transferred to spermidine to form spermine. Hence, putrescine serves as a precursor to spermidine and spermine. Additionally, putrescine has been shown to have a marked regulatory effect upon the polyamine biosynthetic pathway. Also an increased synthesis of putrescine has been shown to be an early indication that a tissue will undergo renewed growth processes. Cadaverine, which is the decarboxyl-ation product of lysine, has been shown to stimulate theactivity of S-adenosylmethionine decarboxylase and is known to be essential to the growth processes of many 117~
microorganisms, for example, H. parainfluenza.
The rationale of polyamine metabolism has been suggested by Cohen, Science 205, 964 (1979). The apparent unique role of polyamine metabolism in trysano-somes and the dependence of trysanosomes upon ornithinedecarboxylase as a source of putrescine further supports our observations that certain specific ornithine de-carboxylase inhibitors of polyamine synthesis are highly effective in inhibiting the growth of protozoa.
SUMMARY OF THE INVENTION
We have discovered that certain compounds that belong to a class of irreversible inhibitors of ornithine de-carboxylase are useful in inhibiting the growth of protozoa.
Moreover, this inhibition occurs throughout a wide spectrum of protozoa such as with members of the subphylum Sarcomastigophora and Sporozoa. More particularly, the class of compounds hereinafter described are particularly useful in inhibiting the growth of members of the super-class of Mastigophora, specifically Trypanosoma brucei brucei and members of the class of Telosporea, specifically Eimeria tenella the organism which causes cocidiosis in poultry.
The compounds useful in the practice of this invention are a-substituted amines or a-substituted-a-amino acids having the general formula y Z-C-R
(I) wherein Rl is hydrogen or carboxy; Y is selected from the group consisting of CH2F, CHF2, CF3 and C-CH; 2 is , - M-1076-Cl ~7~ ;3 selected from the group consisting of H2N-~CH2)3, H2N-CH-(CH2)~ and H2N-CH2CH=CH; with the proviso that when Rl is hydrogen, Y cannot be CF3 and Z must be H2N-CH-(CH2)2; and the salts and individual optical isomers thereof.
When administered 1n vivo to animals containing active protozoal infections, the compounds of formula (I) can be utilized to treat such animals by inhibiting the further growth of the protozoal infections. Alternatively, the compounds described above can be administered prophylactically to prevent such protozoal infections from occurring.
DETAILED DESCRIPTION OF THE INVENTION
In general formula (I) above the symbol Rl is represented either by hydrogen or a carboxyl group. Where the symbol Rl is hydrogen a class of a-substituted amines is delineated. Where the symbol Rl is the carboxyl group, a class of ~-substituted-~-amino acids is delineated.
The symbol Y represents either an acetylenic group or a fluoro-substituted methyl group. The fluoro-substi-tuted methyl groups are illustrated by the monofluoro-methyl, difluoromethyl or trifluoromethyl radicals.
The symbol Z represents either the 3-aminopropyl group, the 3-amino-3-methylpropyl group or the 3-amino-1-propylene group. The saturated groups, viz. the 3-amino-propyl group and the 3-amino-3-methylpropyl group represent the preferred side chains.
M-1076-Cl ~L7~6~3 The proviso limitation is intended to exclude certain classes of diamines from the scope of compounds encom-passing this invention. Excluded from the invention via this proviso limitation are ~-substituted diamines where-in the symbol Z is the 3-aminopropyl group or the 3-amino-l-propylene group, i.e., those compounds having the general formulae y H2N- (CH2) 3-CH-NH2 (II) and y H2N-CH2CH=cH-cH-NH2 (III) wherein the symbol Y is as previously defined.
Specifically excluded from the remaining ~-substituted diamines is the species wherein the symbol Y represents the trifluoromethyl group. Thus, compound (IV), 4-methyl-1-trifluoromethyl-1,4-butanediamine, is specifically excluded from the scope of compounds which can be usefully employed.
C,F3 H2N-C,H- (CH2) 2-CH-NH2 (IV) Included within the scope of compounds that can be employed are ~-substituted amino acids having the formula:
:, Y, H2N-(CH2)3-C-COOH
(V) M-1076-Cl ~17.~ 3 H2N--CH- (CH2) 2-C--COOH
CH3 ~H2 (VI) and y H2N-CH2CH=CH-C-COOH
(VII) In formulae (V), (VI) and (VII) above, the symbol Y is as previously defined.
The ~-substituted amines included within the scope of compounds that can be usefully employed in the practice of this invention are defined by the general formula y H2N-CH- (CH2) 2-CH--NH2 (VIII) wherein the symbol Y represents the CH2F, CHF2 and C--CH
groups, but in the case of the diamines exludes the CF3 group.
Illustrative examples of the salts of the compounds of this invention include non-toxic acid addition salts formed with inorganic acids, such as, hydrochloric, hydrobromic, sulfuric and phosphoric acid, and organic acids, such as, methanesulfonic, salicyclic, maleic, malonic, tartaric, citric, cyclamic and ascorbic acids.
~7~3 M-1076-cl A preferred class of compounds of this invention are those compounds in which the symbol Y represents the difluoromethyl group. Another preferred class of com-pounds is delineated where the symbol Z represents the 3-aminopropyl moiety or the 3-amino-3-methylpropyl moiety.
In addition to the salts indicated above, the term salts is taken to include those internal salts or zwitter-ions of those compounds of formula (I) above that are amphoteric in nature. Moreover, whereas the optical configuration for the compounds described herein is not specifically designated, it is recognized that the ~-carbon atom possesses an asymmetric center and that individual optical isomers of these compounds exist. Accordingly, both the d- and l-optical isomers as well as the racemic mixtures are contemplated as being within the scope of this invention Lactam formation can occur where the symbol Rl represents the carboxyl group and the symbol Z represents the 3-aminopropyl moiety or the 3-amino-3-methylpropyl moiety as represented by the following general formula I
Y - C -- C = O
(CH2)3 NH
(IX) In the above general formula the symbol Y is as originally described. Where the symbol Z represents the 3-amino-3-methylpropyl moiety, the (CH2)3 group in formula (IX) above can be additionally substituted with a 3-methyl group.
~Lf.7a~3 M-1076-Cl Illustrative examples of compounds useful in accordance with the teachings of this invention include:
2,5-diamino-2-(fluoromethyl)pentanoic acid, 2,5-diamino-2-(difluoromethyl)pentanoic acid, 2,5-diamino-2-(trifluoromethyl)pentanoic acid, 2,5-diamino-2-(ethynyl)pentanoic acid, 2,5-diamino-2-fluoromethyl-5-methylpentanoic acid, 2,5-diamino-2-difluoromethyl-5-methylpentanoic acid, 2,5-diamino-2-trifluoromethyl-5-methylpentanoic acid, 2,5-diamino-2-ethynyl-5-methylpentanoic acid, 2,5-diamino-2-fluoromethyl-3-pentenoic acid, 2,5-diamino-2-difluoromethyl-3-pentenoic acid, 2,5-diamino-2-trifluoromethyl-3-pentenoic acid, 2,5-diamino-2-ethynyl-3-pentenoic acid, 1-fluoromethyl-4-methyl-1,4-butanediamine, 2-difluoromethyl-4-methyl-1,4-butanediamine, and l-ethynyl-4-methyl-1,4-butanediamine.
The compounds of general formula (I) wherein Z is H2N-(CH2)3; Y is CH2F, CHF2 and CF3, and Rl is carboxy are prepared by treating respectively an ester derivative of ornithine, wherein the amino groups are suitably pro-tected, with a strong base to form the carbanion inter-mediate. This is reacted with a suitable halomethyl-halo alkylating reagent in an aprotic solvent, such as di-methylsulfoxide, dimethylformamide, dimethylacetamide, benzene, toluene, ethers, such as, tetrahydrofuran, diethyl ether or dioxane, and in the presence of a hexamethylphosphortriamide when Y is other than F2CH-, at a temperature of about -120C to 120C, preferably about 25 to 50C, for about 1/2 hour to 48 hours followed by acid or base hydrolysis. This can be represented by the following reaction sequence.
.
. M-1076-Cl '16~3 g Zl-,CH-COOR2 Zl-C( ) COOR2 R4 strong base~ ' N=C-R3 compounds 1 alkylating reagent ~ ~0 Y, Y
z2-C-COOR2dilute aqueous Zl-C-COOR2 NH2~ acld/hydrazine_ N=,C-R3 compounds 3 compounds 2 I(acid/base) H2N-tcH2)3-c-cooH
(Formula V) In the above reaction sequence Y is FCH2-, F2CH-, F3C-; R2 is a lower alkyl group, for example, methyl, ethyl, isopropyl, n-propyl or n-butyl; R3 is hydrogen, phenyl, a straight or branched alkyl group having from 1 to 8 carbon atoms, methoxy or ethoxy; R4 is phenyl or a straight or branched alkyl group of from 1 to 8 carbon atoms; or R3 and R4 taken together may form an alkylene group of from 5 to 7 carbon atoms, that is, -CH2-(CH2)m-CH2- wherein m is an integer of from 3 to 5.
Illustrative examples of straight or branched alkyl groups of from 1 to 8 carbon atoms which R3 and R4 may M-1076-Cl ~17~6~3 represent are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, neopentyl or triethylmethyl groups. The symbol Zl is R3-C=N(CH2)3-, O o R4 Rs-CN~(CH2)3- or R6-OCNH(CH2)3-; R3 and R4 are the same and have the meanings defined above; and each of Rs and R6 is phenyl, benzyl or a lower alkyl group of from 1 to 4 carbon atoms that is straight or branched, for example, methyl, ethyl or isopropyl; Z2 is H2N(CH2)3-, O O
Rs-CNH(CH2)3- or R6-OCNH(CH2)3- wherein Rs and R6 have the above defined meanings.
Suitable strong bases which may be employed in the above reaction se~uence to form the carbanion intermediate are those which will abstract a proton from the carbon atom alpha to the carboxy group, such as, alkyl lithium, for example, butyl lithium or phenyl lithium, lithium di-alkylamide, for example, lithium diisopropylamide, lithium amide, tertiary potassium butylate, sodium amide, metal hydrides, for example, sodium hydride or potassium hydride, tertiary amines, such as, triethylamine, lithium acetylide or dilithium acetylide. Lithium acetylide, dilithium acetylide, sodium hydride, and lithium diiso-propylamide are particularly preferred bases.
Suitable alkylating reagents which may be employed in the above reaction sequence are illustratively chloro-fluoromethane, bromofluoromethane, fluoroiodomethane, chlorodifluoromethane, bromodifluoromethane, difluoro-iodomethane, bromotrifluoromethane, chlorotrifluoromethane, trifluoroiodomethane, bromochloromethane, dichloromethane, chloroiodomethane, bromodichloromethane and dichloroiodo-methane. These alkylating reagents ~re well known to the art.
- M-1076-Cl 1~7'~ 3 Removal of the protecting groups of the amine and carboxylic acid function may be achieved in one step by treatment of compound 2 with aqueous acid, for example, hydrochloric acid or toluenesulfonic acid, at a tempera-ture of about 0 to 100C for about 4 to 24 hours to give compounds of general Formula V. It is preferred to remove first the protecting groups of the amine function(s) of compounds 2 when said functions are pro-tected as a Schiff's base by treating compounds 2 with dilute aqueous acid, for example, hydrochloric acid or with hydrazine or phenylhydrazine in solvents, such as, lower alcohols, for example, methanol or ethanol, ethers, chlorinated hydrocarbons, benzene and water. Remova of the protecting groups of the carboxylic acid function and the amine groups when the amine groups are protected other than as a Schiff's base is achieved by treatment of compounds 3 with concentrated aqueous acids, for example, hydrobromic acid at a temperature of about 0 to 100C or in aqueous base, for example, ammonium hydroxide.
The amine protected ester derivatives, that is, compounds 1, wherein R3 is other than methoxy or ethoxy, are prepared by treating an appropriate amino acid ester with a carbonyl bearing compound to form a Schiff's base in a generally known manner, specifically: (a) when R3 is hydrogen, by treating the appropriate amino acid ester with benzaldehyde or an alkanal having from 1 to 9 carbon atoms being straight or branched, for example, 1-propanal, l-butanal, 2,2-dimethylpropan-1-al or 2,2-diethylbutan-l-al; (b) when R3 is phenyl by treating the appropriate amino acid ester with benzophenone or phenyl alkyl ketone wherein the alkyl moiety has from 1 to 8 carbon atoms and is straight or branched, for example, phenyl methyl ketone, phenyl ethyl ketone, phenyl isopropyl ketone, phenyl n-butyl ketone or phenyl tert-.
3L~746~3 butyl ketone; and (c) when R3 is a straight or branched alkyl group having from 1 to 8 carbon atoms, treating the appropriate amino acid ester with a phenyl alkyl ketone as described above or with a di-alkyl ketone wherein each alkyl moiety has from 1 to 8 carbon atoms and is straight or b anched, for example, dimethyl ketone, diethyl ketone, methyl isopropyl ketone, di-n-butyl ketone or methyl tert-butyl ketone. The carbonyl bearing compounds are known in the art or may be prepared by procedures well known in the art.
When R3 is methoxy or ethoxy in compound 1, an appropriate amino acid ester derivative is reacted with benzoyl halide or an alkanoic acid halide wherein the alkanoic acid has from 1 to 9 carbon atoms and may be lS straight or branched, such as, acetyl chloride, propionyl chloride, butyryl chloride, tert-butyrl chloride, 2,2-diethylbutyric acid chloride or valeryl chloride. The reaction is conducted at 0C in an organic solvent such as ether, methylenechloride, dimethylformamide, dimethyl-acetamide or chlorobenzene in the presence of an organic base such as triethylamine or pyridine. ~ollowing the reaction, the reaction mixture is allowed to warm to about 25C for one hour. The resulting amide derivative is combined with an alkylating reagent, such as methyl-fluorosulfonate, dimethylsulfate, methyliodide, methyl ~-toluenesulfonate or trimethyloxonium hexafluorophosphate (when R3 is methoxy) or triethyloxonium tetrafluoroborate (when R3 is ethoxy) at about 25C in a chlorinated hydro-carbon solvent such as methylene chloride, chlorobenzene or chloroform. The reaction mixture is refluxed for about 12 to 20 hours, cooled to about 25C and an organic base such as triethylamine or pyridine is added after which the solution is extracted with brine and the product isolated.
a~
The compounds of general formula (I) wherein Z is H2N-(CH2)3; Y is CH2F, CHF2 and CF3, and Rl is carboxy are prepared by treating respectively an ester derivative of ornithine, wherein the amino groups are suitably pro-tected, with a strong base to form the carbanion inter-mediate. This is reacted with a suitable halomethyl-halo alkylating reagent in an aprotic solvent, such as di-methylsulfoxide, dimethylformamide, dimethylacetamide, benzene, toluene, ethers, such as, tetrahydrofuran, diethyl ether or dioxane, and in the presence of a hexamethylphosphortriamide when Y is other than F2CH-, at a temperature of about -120C to 120C, preferably about 25 to 50C, for about 1/2 hour to 48 hours followed by acid or base hydrolysis. This can be represented by the following reaction sequence.
.
. M-1076-Cl '16~3 g Zl-,CH-COOR2 Zl-C( ) COOR2 R4 strong base~ ' N=C-R3 compounds 1 alkylating reagent ~ ~0 Y, Y
z2-C-COOR2dilute aqueous Zl-C-COOR2 NH2~ acld/hydrazine_ N=,C-R3 compounds 3 compounds 2 I(acid/base) H2N-tcH2)3-c-cooH
(Formula V) In the above reaction sequence Y is FCH2-, F2CH-, F3C-; R2 is a lower alkyl group, for example, methyl, ethyl, isopropyl, n-propyl or n-butyl; R3 is hydrogen, phenyl, a straight or branched alkyl group having from 1 to 8 carbon atoms, methoxy or ethoxy; R4 is phenyl or a straight or branched alkyl group of from 1 to 8 carbon atoms; or R3 and R4 taken together may form an alkylene group of from 5 to 7 carbon atoms, that is, -CH2-(CH2)m-CH2- wherein m is an integer of from 3 to 5.
Illustrative examples of straight or branched alkyl groups of from 1 to 8 carbon atoms which R3 and R4 may M-1076-Cl ~17~6~3 represent are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, neopentyl or triethylmethyl groups. The symbol Zl is R3-C=N(CH2)3-, O o R4 Rs-CN~(CH2)3- or R6-OCNH(CH2)3-; R3 and R4 are the same and have the meanings defined above; and each of Rs and R6 is phenyl, benzyl or a lower alkyl group of from 1 to 4 carbon atoms that is straight or branched, for example, methyl, ethyl or isopropyl; Z2 is H2N(CH2)3-, O O
Rs-CNH(CH2)3- or R6-OCNH(CH2)3- wherein Rs and R6 have the above defined meanings.
Suitable strong bases which may be employed in the above reaction se~uence to form the carbanion intermediate are those which will abstract a proton from the carbon atom alpha to the carboxy group, such as, alkyl lithium, for example, butyl lithium or phenyl lithium, lithium di-alkylamide, for example, lithium diisopropylamide, lithium amide, tertiary potassium butylate, sodium amide, metal hydrides, for example, sodium hydride or potassium hydride, tertiary amines, such as, triethylamine, lithium acetylide or dilithium acetylide. Lithium acetylide, dilithium acetylide, sodium hydride, and lithium diiso-propylamide are particularly preferred bases.
Suitable alkylating reagents which may be employed in the above reaction sequence are illustratively chloro-fluoromethane, bromofluoromethane, fluoroiodomethane, chlorodifluoromethane, bromodifluoromethane, difluoro-iodomethane, bromotrifluoromethane, chlorotrifluoromethane, trifluoroiodomethane, bromochloromethane, dichloromethane, chloroiodomethane, bromodichloromethane and dichloroiodo-methane. These alkylating reagents ~re well known to the art.
- M-1076-Cl 1~7'~ 3 Removal of the protecting groups of the amine and carboxylic acid function may be achieved in one step by treatment of compound 2 with aqueous acid, for example, hydrochloric acid or toluenesulfonic acid, at a tempera-ture of about 0 to 100C for about 4 to 24 hours to give compounds of general Formula V. It is preferred to remove first the protecting groups of the amine function(s) of compounds 2 when said functions are pro-tected as a Schiff's base by treating compounds 2 with dilute aqueous acid, for example, hydrochloric acid or with hydrazine or phenylhydrazine in solvents, such as, lower alcohols, for example, methanol or ethanol, ethers, chlorinated hydrocarbons, benzene and water. Remova of the protecting groups of the carboxylic acid function and the amine groups when the amine groups are protected other than as a Schiff's base is achieved by treatment of compounds 3 with concentrated aqueous acids, for example, hydrobromic acid at a temperature of about 0 to 100C or in aqueous base, for example, ammonium hydroxide.
The amine protected ester derivatives, that is, compounds 1, wherein R3 is other than methoxy or ethoxy, are prepared by treating an appropriate amino acid ester with a carbonyl bearing compound to form a Schiff's base in a generally known manner, specifically: (a) when R3 is hydrogen, by treating the appropriate amino acid ester with benzaldehyde or an alkanal having from 1 to 9 carbon atoms being straight or branched, for example, 1-propanal, l-butanal, 2,2-dimethylpropan-1-al or 2,2-diethylbutan-l-al; (b) when R3 is phenyl by treating the appropriate amino acid ester with benzophenone or phenyl alkyl ketone wherein the alkyl moiety has from 1 to 8 carbon atoms and is straight or branched, for example, phenyl methyl ketone, phenyl ethyl ketone, phenyl isopropyl ketone, phenyl n-butyl ketone or phenyl tert-.
3L~746~3 butyl ketone; and (c) when R3 is a straight or branched alkyl group having from 1 to 8 carbon atoms, treating the appropriate amino acid ester with a phenyl alkyl ketone as described above or with a di-alkyl ketone wherein each alkyl moiety has from 1 to 8 carbon atoms and is straight or b anched, for example, dimethyl ketone, diethyl ketone, methyl isopropyl ketone, di-n-butyl ketone or methyl tert-butyl ketone. The carbonyl bearing compounds are known in the art or may be prepared by procedures well known in the art.
When R3 is methoxy or ethoxy in compound 1, an appropriate amino acid ester derivative is reacted with benzoyl halide or an alkanoic acid halide wherein the alkanoic acid has from 1 to 9 carbon atoms and may be lS straight or branched, such as, acetyl chloride, propionyl chloride, butyryl chloride, tert-butyrl chloride, 2,2-diethylbutyric acid chloride or valeryl chloride. The reaction is conducted at 0C in an organic solvent such as ether, methylenechloride, dimethylformamide, dimethyl-acetamide or chlorobenzene in the presence of an organic base such as triethylamine or pyridine. ~ollowing the reaction, the reaction mixture is allowed to warm to about 25C for one hour. The resulting amide derivative is combined with an alkylating reagent, such as methyl-fluorosulfonate, dimethylsulfate, methyliodide, methyl ~-toluenesulfonate or trimethyloxonium hexafluorophosphate (when R3 is methoxy) or triethyloxonium tetrafluoroborate (when R3 is ethoxy) at about 25C in a chlorinated hydro-carbon solvent such as methylene chloride, chlorobenzene or chloroform. The reaction mixture is refluxed for about 12 to 20 hours, cooled to about 25C and an organic base such as triethylamine or pyridine is added after which the solution is extracted with brine and the product isolated.
a~
3 M- l ~ 7 6 - C I
When R3 and R4 together form an alkylene group in compounds 1 having from 5 to 7 carbon atoms, the corresponding amino acid ester derivatives are obtained by treating the amino acid ester with a cyclic alkanone to form a Schiff's base by procedures generally known in the art. Cyclic alkanones that can be employed include cyclopentanone, cyclohexanone and cycloheptanone.
o When the symbol Zl in compounds 1 is RsCNH(CH2)3-O O O
or R6OCNH(CH2)3-, the -CRs and -COR6 protecting groups are added to the corresponding free amino acid, i.e., ornithine, by treatment of said amino acid with an excess of a copper salt, such as copper carbonate, in boiling water for about 1 to 6 hours. Upon cooling to room temperature the insoluble materials are filtered and the filtrate is treated with an appropriate acid halide o (when Zl is RsCNH(CH2)n-) or an appropriate alkyl or aryl haloformate (when Zl is R6OCNH(CH2)n-), in a solvent such as acetone in the presence of a base sush as sodium bicarbonate or sodium hydroxide. This treatment is followed by treatment with hydrogen sulfide. Illustra-tive acid halides which may be employed include acetyl chloride, propionyl chloride, benzoyl chloride or 2-phenylacetyl chloride. Illustrative haloformates which may be employed include benzyl chloroformate, phenyl chloroformate, methyl chloroformate or ethyl chloroformate.
The lactams of the compounds of general Formula I
wherein Rl is carboxy are prepared from the corresponding amino acid esters having the structure y H2N(CH2)3-C-cOR7 (X) wherein Y has the meaning defined in Formula I and R7 is a straight or branched alkoxy group of from 1 to 8 carbon atoms, illustratively methoxy, ethoxy, isopropoxy, M-1076-Cl ~a17466?3 butoxy or hexyloxy. The lactams are prepared by treating said amino acid esters with an appropriate base, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium amide, or an organic amine such as a trialkylamine, for example, triethylamine in a solvent such as a lower alcohol, for example, methanol, ethanol, isopropyl alco-hol, n-butanol, water, dimethylformamide, dimethylsulfoxide, hexamethylphosphortriamide or mixtures thereof. The reaction is conducted for a period of from 1/2 hour to 24 hours at a temperature of from about 0 to 120C, optionally under a nitrogen atmosphere. The compounds of general Formula (X) are obtained by procedures well known to the art, for example, by utilizing the corresponding amino acid and treating said amino acid with an appropriate alcohol such as methanol, ethanol, isopropyl alcohol, n-butanol or n-heptanol saturated with HCl gas.
The compounds of general formula I wherein Z is H2N-CH~CH2)2; Y is CH2F, CHF2 and CF3, and R1 is carboxy are prepared via procedures that are analogous to those just described.
Compounds of general Formula I wherein Z is H2N-CH(CH2)2 or H2N-(CH2)3, Y is C CH and Rl is carboxy are prepared by treating a suitably protected propargylamine derivative, such as a silyl derivative, with a strong base to form a protected propargylamine carbanion intermediate. This carbanion intermediate is reacted with an alkylating reagent of the formula RgX, wherein X is a halogen such as chlorine or bromine, and R8 is PhHC=N(CH2)n~ in which n is the integer 3. The thus formed alkylated protected propargylamine derivative is then treated with a strong base to form an M-1076-Cl ~746~3 alkylated protected propargylamine carbonaion. The second carbanion is reacted with an acylating reagent and the protecting groups are subsequently removed by.
acid or base hydrolysis as indicated in the following reaction scheme:
(Rg)3-Si-c-c-clH2 strong (Rg)3-Si-C--C-CH( ) N=C,-Rll base ~ N=C~-Rll Rlo ,Rlo compounds 4 ~Rgx (R7)3-si-c~c-cq-) strong (Rg)3-Si-C=c-cH
N=C-Rll ~base N=C-Rll Rll) , Rlo acylating compounds 5 !reagent ,R8 z (Rg)3-Si-C~C-C-R12 H2o HC~C-C-COOH
~ (acid/base) Rlo compounds 6 Formula XI
In the above reaction scheme R~ and X have the meanings defined hereinabove, Ph represents phenyl, R1o is hydrogen, methoxy or ethoxy, Rll is phenyl, tert-butyl, or triethyl-methyl, Rg is a straight or branched lower alkyl group having from 1 to 4 carbon atoms, R12 is a carboxy anion, M-1076-Cl ~7~3 a carboxylic acid ester, a carboxamide, a nitrile or other group capable of being hydrolyzed to a carboxylic acid function, and Z is H2N-c-(cH2)2 or H2~(C~2)3-Suitable strong bases which may be employed in the above reaction to form each carbanion are those which will abstract a proton from the carbon atom adjacent to the acetylene moiety, such as an alkyl lithium. Suitable alkylithium compounds that may be employed include butyl lithium or phenyl lithium, lithium diisopropylamide, lithium amide, tertiary potassium butylate and sodium amide.
The alkylating reagents, RgX, employed in the above reaction are known to the art and can be prepared by standard procedures known in the art. Thus, the reactant PhHC=N(CH2)n~ can be prepared, for example, by reacting 3-bromo-n-propylamine hydrochloride or 4-bromo-n-butylamine hydrochloride with benzaldehyde in the presence of an organic amine, such as, triethylamine in a suitable solvent.
Solvents that can be employed include diethyl ether, tetra-hydrofuran, dioxane, chloroform or dichloromethane.
Suitable acylating reagents which may be employed in the above reaction are halo-formates, such as chloro methylformate or chloro ethylformate, azido tert-butyl-formate, cyanogen bromide, carbon dioxide, diethylcarbonate, phenylisocyanate, triethoxymethylium tetrafluoroborate, N,N-dimethylcarbamoyl chloride, 2-methylthio-1,3-dithio-linium iodide, ethylene carbonate or ethylene trithio-carbonate. When 2-methylthio-1,3-dithiolinium iodide is employed the additional step of alcoholysis by means of a lower alcohol, such as ethanol or isopropyl alcohol is required prior to hydrolysis of the protecting groups.
The alkylating reaction is readily conducted in the presence of an aprotic solvent such as benzene, toluene, ether, tetrahydrofuran, dimethylsulfoxide, dimethylform-amide, dimethyl acetamide, hexamethyl phosphortriamide.
M-1076-Cl :~17~6~3 The reaction temperature varies from -120C to about 25C, a preferred reaction temperature being about -70C, with the reaction period ranging frvm about l/2 hour to 24 hours.
Removal of the protecting groups, as represented in the foregoing reaction scheme in the step relating to the conversion of compounds 6 to the compounds of Formula XI, is achieved by treatment of compounds 6 with an aqueous acid such as hydrochloric acid or toluene sulfonic acid.
Alternatively, an aqueous base such as sodium hydroxide or potassium hydroxide, or hydrazine or phenylhydrazine may be employed.
The propargylamine derivatives of compounds 4 wherein Rlo is hydrogen are prepared by the addition of protecting groups on the acetylene function and the nitrogen function of propargylamine. Protection of the nitrogen function of the propargylamine is accomplished by forming a Schiff's base with a nonenolizable carbonyl bearing compound such as benzaldehyde, 2,2-dimethylpropanal or 2,2-diethylbutanal.
Protection of the acetylenic function is accomplished by reacting the above-described Schiff's base with a tri-alkylsilyl chloride wherein the alkyl moiety has from l to 4 carbon atoms and is either straight or branched.
Trialkylsilyl chlorides that can be utilized include trimethylsilylchloride or triethylsilylchloride.
The propargylamine derivatives of compounds 4, wherein Rlo is methoxy or ethoxy are prepared by reacting propar-gylamine wherein the acetylene function is protected by a trialkylsilyl group with benzoyl chloride, pivalic acid chloride, or 2,2-diethylbutyric acid chloride at 0C in a suitable solvent. Suitable solvents include diethyl ether, dioxane, tetrahydrofuran, chloroform, methylenechloride, dimethylformamide, dimethylacetamide, or chlorobenzene.
The reaction is conducted in the presence of an organic base such as triethylamine or pyridine after which the reaction mixture is allowed to warm to about 25C for .
M-1076-Cl 6~3 one hour. The resulting amide derivative is combined with an alkylating reagent, such as, methylfluorosulfonate, dimethylsulfate, methyliodide, methyl p-toluenesulfonate or trimethyloxonium hexafluorophosphate when Rlo is methoxy, or triethyloxonium tetrafluoroborate when Rlo is ethoxy, at about 25C in a chlorinated hydrocarbon solvent such as methylene chloride, chlorobenzene or chloroform.
The reaction mixture is refluxed for about 12 to 20 hours, cooled to about 25C and an organic base such as triethyl-amine or pyridine is added. The resulting solution isextracted with brine and the desired product isolated therefrom.
The protected propargylamine starting material is obtained by treating a 3-trialkylsilylprop-2-ynyl-1-imino-benzyl derivative, that is compounds 4 wherein Rlo ishydrogen and Rll is phenyl, with hydrazine or phenylhydra-zine at about 25C for about 1/2 hour after which the mixture is diluted with, for example, petroleum ether, benzene or toluene and the amine isolated. Alternatively, the imine is hydrolyzed with 0.5 to 1 N HCl solution, an~
the aqueous phase evaporated to afford the amine as the hydrochloride salt.
Compounds of formula I wherein Z is H2N-CH(CH2)2;
Y is CH2F or CHF2; and Rl is hydrogen are prepared by reducing a ketone of the formula o Z '--C--Y
(XII) ,R13 R113 wherein Z' is phthaloyl-NCH(CH2)2-, benzoyl-NHCH(CH2)2-, - M-1076-Cl ~17~3 R,13 R,13 alkanoyl-NHCH(CH2)2-, alkoxycarbonyl-NHCH(CH2)2- or R,l~
benzyloxycarbonyl-NHCH(CH2)2- wherein the alkanoyl moiety has from 2 to 5 carbon atoms and is straight or branched, the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched, Y is CH2F and CHF2 and R13 is methyl.
The ketones are reduced to the corresponding alcohol which is treated with one equivalent of an imide, such as, phthalimide, succinimide or maleimide, 1.1 equivalents of a phosphine, for example, triphenylphosphine or a trialkylphosphine, such as, tri-n-butylphosphine and 1.1 equivalents of diethyl azodicarboxylate in a suitable solvent. Suitable solvents include ethers such as diethyl ether, tetrahydrofuran or ~-dioxane, benzene or dimethoxy-ethane. The reaction is conducted at about 0 to 100C, preferably about 25C, for a period of about one-half hour to 24 hours under an inert atmosphere such as nitrogen or argon. The thus obtained imido derivative is then hydrolyzed to the free amine.
The compounds of general formula (XII) wherein Y is FCH2- are prepared by treating a compound of the formula R
z ' -C-CH2R14 (XIII) wherein Z' is defined as above and R14 is a suitable leaving group, such as chlorine, bromine or iodine, mesylate, tosylate, triflate or trifluoroacetate with an appropriate fluorinating reagent, such as, potassium fluoride, silver fluoride, cesium fluoride, thallium fluoride, tetrabutylammonium fluoride in a suitable solvent. Suitable solvents include solvents such as M-1076-Cl 3L174~;Q3 dimethoxyethane, dimethylsulfoxide, dimethylformamide, ethylene glycol, acetonitrile, acetone, benzene or hydrogen fluoride. The reaction is conducted at a temperature of from about 0 to 200C for a period of about 2 to 48 hours.
The leaving group Rl4 may also be a diazo group in which case the fluorinating reagent employed is hydrogen fluor-ide/pyridine. Suitable solvents for the reaction wherein R14 is a diazo group are aprotic solvents such as diethyl ether, tetrahydrofuran and pentane. The reaction time varies from about 30 minutes to 24 hours at a temperature ranging from about -20 to 65C. Illustratively, a com-pound of the formula o Z '-C-R14 as defined above wherein Rl4 is a diazo group in a suitable aprotic solvent is added to a solution of hydrogen fluor-ide/pyridine and cooled to -10C. The reaction mixture is stirred vigorously at -10C for l hour, warmed to about 25C for 2 hours and then poured over ice. The organic phase is separated, washed with a base such as sodium bicarbonate, dried over magnesium sulate and concentrated under vacuum to afford the appropriate fluoromethyl ketone derivative of formula (XII).
The diazo ketone derivatives, that is, the compounds of formula (XIII) wherein R14 is a diazo group, can be obtained via the corresponding acid halide represented by a compound of the formula o Z'-C-halide wherein halide may be, for example, chloride and Z' has the meaning defined in formula (XII). The acid halide contained in an aprotic solvent, as for example diethyl ether, tetrahydrofuran, pentane, hexane, benzene, dimeth-oxyethane or dioxane, is added to a solution of diazo-methane in ether cooled to about -~0 to 20C, followed M-1076-Cl -21- 1174~3 by vigorous stirring at about 25C for about l to 24 hours. The diazo ketone derivative so obtained can be isolated using standard procedures such as evaporation of the solvent with subsequent purification by recrystallization or chromatography. ~lternatively, the reaction mixture can be treated with an appropriate fluorinating reagent as described above without isolation.
The appropriately substituted diazo ketone derivative described above can be used to prepare compounds of formula (XIII) wherein R14 is, for example, halogen, mesylate, tosylate, triflate, or trifluoroacetate using procedures generally known to the art. To obtain compounds of general formula (XIII) wherein R14 is halogen, such as, chlorine, bromine, or iodine the corresponding compound of formula (XIII) in which Rl4 is a diazo group is treated with either aqueous hydrogen chloride, hydrogen bromide or hydrogen iodide in a suitable aprotic solvent. In order to obtain compounds of formula (XIII) wherein Rl4 is mesylate, tosylate, triflate or trifluoroacetate, the corresponding diazo ketone derivative, wherein R14 is a diazo group is dissolved in a suitable aprotic solvent and treated with dilute sulfuric acid to yield the corresponding benzyl methanol ketone derivative. Lastly, the benzyl methanol ketone is esterified with an appropriate acid chloride or acid anhydride utlizing methane sulfonic acid, p-toluene sulfonic acid, tri-fluoromethyl sulfonic acid or trifluoroacetic acid.
The acid halides, that is, compounds of the formula o Z'-C-halide as described above, are known compounds which can be pre-pared from the corresponding acids. Thus, for example, M-1076-Cl ~'7~ 33 treatment of the appropriate acid with thionyl chloride in an aprotic solvent, such as, diethyl ether, tetra-hydrofuran, benzene or dichloromethane at a temperature ranging from about 0C to the reflux temperature of the solvent for about 1 to 24 hours results in the foundation of the corresponding acid halide. Alternatively, treat-ment of the appropriate acid with oxalyl chloride in one of the aprotic solvents described above at a temperature of about 0 to 40C for about 1 to 24 hours also results in the preparation of the corresponding acid halide.
The compounds of general formula (XII) wherein Y
Rl is FCH2- and Z' is other than benzoyl-NHC(CH2)2- or ,Rl alkanoyl-NHC(CH2)2- may also be obtained by treating a compound of the formula z2-Rl5 (XIV) R,13 wherein Z2 is phthaloyl-N-CH(CH2)2-, alkoxycarbonyl-R,13 R,13NHC(CH2)2-, benzyloxycarbonyl-NHC(CH2)2-, ~-methylthioethyl or ~-benzylthioethyl; R13 is methyl; and Rls is chlorine, bromine or iodine, mesylate or tosylate. Thus, a compound of formula (XIV) is reacted with triphenylphosphine or tri-(lower)-alkylphosphine, for example, tri-n-butyl-phosphine, in a solvent such as benzene, toluene, methanol, ethanol, acetonitrile, tetrahydrofuran, diethyl ether or dimethoxyethane. The reaction is conducted at a temperature ranging from 25C to the reflux temperature of the solvent M-1076-Cl for ajperiod ranging from about 10 minutes to 48 hours.
On cooling the precipitate which forms is washed with solvent and recrystallized to give the appropriate phos-phonium salt. The triphenylphosphonium or trialkylphos-phonium salt is added to an excess (up to 25%) of sodiumor lithium metal dissolved in liquid ammonia to which a catalytic amount of ferric nitrate is added. Stirring is continued for about 10 minutes to 3 hours after which the ammonia is evaporated under an inert atmosphere, such as, nitrogen or argon. An appropriate solvent, such as, benzene, toluene, diethyl ether, tetrahydrofuran or di-methoxyethane is added and the resulting substituted methylidenephosphorane is collected. The methylidene-phosphorane is treated with a lower alkyl ester of mono-fluoroacetic acid in a solvent such as benzene, toluene,diethyl ether, tetrahydrofuran or dimethoxyethane. The reaction is conducted under an inert atmosphere such as nitrogen or argon at a temperature ranging from about 0C
to the reflux temperature of the solvent for a period of from about 30 minutes to 24 hours. The reaction mixture is concentrated by distillation to yield an olefin. The olefin is treated with an aqueous mineral acid, such as hydrochloric or hydrobromic acid or an organic acid such as trifluoroacetic acid or ~-toluene sulfonic acid in the presence of a cosolvent such as tetrahydrofuran, diethyl ether, or benzene for a period of from about 30 minutes to 24 hours at a temperature ranging from about 0C to the reflux temperature of the solvent. The amount of acid employed may vary from a catalytic amount to a concentrated acid solution.
As used in general formula (XIV) the term phthaloyl-N-CH(CH2)2- is taken to mean the group o C Rl 3 ~-~ M-1076-Cl
When R3 and R4 together form an alkylene group in compounds 1 having from 5 to 7 carbon atoms, the corresponding amino acid ester derivatives are obtained by treating the amino acid ester with a cyclic alkanone to form a Schiff's base by procedures generally known in the art. Cyclic alkanones that can be employed include cyclopentanone, cyclohexanone and cycloheptanone.
o When the symbol Zl in compounds 1 is RsCNH(CH2)3-O O O
or R6OCNH(CH2)3-, the -CRs and -COR6 protecting groups are added to the corresponding free amino acid, i.e., ornithine, by treatment of said amino acid with an excess of a copper salt, such as copper carbonate, in boiling water for about 1 to 6 hours. Upon cooling to room temperature the insoluble materials are filtered and the filtrate is treated with an appropriate acid halide o (when Zl is RsCNH(CH2)n-) or an appropriate alkyl or aryl haloformate (when Zl is R6OCNH(CH2)n-), in a solvent such as acetone in the presence of a base sush as sodium bicarbonate or sodium hydroxide. This treatment is followed by treatment with hydrogen sulfide. Illustra-tive acid halides which may be employed include acetyl chloride, propionyl chloride, benzoyl chloride or 2-phenylacetyl chloride. Illustrative haloformates which may be employed include benzyl chloroformate, phenyl chloroformate, methyl chloroformate or ethyl chloroformate.
The lactams of the compounds of general Formula I
wherein Rl is carboxy are prepared from the corresponding amino acid esters having the structure y H2N(CH2)3-C-cOR7 (X) wherein Y has the meaning defined in Formula I and R7 is a straight or branched alkoxy group of from 1 to 8 carbon atoms, illustratively methoxy, ethoxy, isopropoxy, M-1076-Cl ~a17466?3 butoxy or hexyloxy. The lactams are prepared by treating said amino acid esters with an appropriate base, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium amide, or an organic amine such as a trialkylamine, for example, triethylamine in a solvent such as a lower alcohol, for example, methanol, ethanol, isopropyl alco-hol, n-butanol, water, dimethylformamide, dimethylsulfoxide, hexamethylphosphortriamide or mixtures thereof. The reaction is conducted for a period of from 1/2 hour to 24 hours at a temperature of from about 0 to 120C, optionally under a nitrogen atmosphere. The compounds of general Formula (X) are obtained by procedures well known to the art, for example, by utilizing the corresponding amino acid and treating said amino acid with an appropriate alcohol such as methanol, ethanol, isopropyl alcohol, n-butanol or n-heptanol saturated with HCl gas.
The compounds of general formula I wherein Z is H2N-CH~CH2)2; Y is CH2F, CHF2 and CF3, and R1 is carboxy are prepared via procedures that are analogous to those just described.
Compounds of general Formula I wherein Z is H2N-CH(CH2)2 or H2N-(CH2)3, Y is C CH and Rl is carboxy are prepared by treating a suitably protected propargylamine derivative, such as a silyl derivative, with a strong base to form a protected propargylamine carbanion intermediate. This carbanion intermediate is reacted with an alkylating reagent of the formula RgX, wherein X is a halogen such as chlorine or bromine, and R8 is PhHC=N(CH2)n~ in which n is the integer 3. The thus formed alkylated protected propargylamine derivative is then treated with a strong base to form an M-1076-Cl ~746~3 alkylated protected propargylamine carbonaion. The second carbanion is reacted with an acylating reagent and the protecting groups are subsequently removed by.
acid or base hydrolysis as indicated in the following reaction scheme:
(Rg)3-Si-c-c-clH2 strong (Rg)3-Si-C--C-CH( ) N=C,-Rll base ~ N=C~-Rll Rlo ,Rlo compounds 4 ~Rgx (R7)3-si-c~c-cq-) strong (Rg)3-Si-C=c-cH
N=C-Rll ~base N=C-Rll Rll) , Rlo acylating compounds 5 !reagent ,R8 z (Rg)3-Si-C~C-C-R12 H2o HC~C-C-COOH
~ (acid/base) Rlo compounds 6 Formula XI
In the above reaction scheme R~ and X have the meanings defined hereinabove, Ph represents phenyl, R1o is hydrogen, methoxy or ethoxy, Rll is phenyl, tert-butyl, or triethyl-methyl, Rg is a straight or branched lower alkyl group having from 1 to 4 carbon atoms, R12 is a carboxy anion, M-1076-Cl ~7~3 a carboxylic acid ester, a carboxamide, a nitrile or other group capable of being hydrolyzed to a carboxylic acid function, and Z is H2N-c-(cH2)2 or H2~(C~2)3-Suitable strong bases which may be employed in the above reaction to form each carbanion are those which will abstract a proton from the carbon atom adjacent to the acetylene moiety, such as an alkyl lithium. Suitable alkylithium compounds that may be employed include butyl lithium or phenyl lithium, lithium diisopropylamide, lithium amide, tertiary potassium butylate and sodium amide.
The alkylating reagents, RgX, employed in the above reaction are known to the art and can be prepared by standard procedures known in the art. Thus, the reactant PhHC=N(CH2)n~ can be prepared, for example, by reacting 3-bromo-n-propylamine hydrochloride or 4-bromo-n-butylamine hydrochloride with benzaldehyde in the presence of an organic amine, such as, triethylamine in a suitable solvent.
Solvents that can be employed include diethyl ether, tetra-hydrofuran, dioxane, chloroform or dichloromethane.
Suitable acylating reagents which may be employed in the above reaction are halo-formates, such as chloro methylformate or chloro ethylformate, azido tert-butyl-formate, cyanogen bromide, carbon dioxide, diethylcarbonate, phenylisocyanate, triethoxymethylium tetrafluoroborate, N,N-dimethylcarbamoyl chloride, 2-methylthio-1,3-dithio-linium iodide, ethylene carbonate or ethylene trithio-carbonate. When 2-methylthio-1,3-dithiolinium iodide is employed the additional step of alcoholysis by means of a lower alcohol, such as ethanol or isopropyl alcohol is required prior to hydrolysis of the protecting groups.
The alkylating reaction is readily conducted in the presence of an aprotic solvent such as benzene, toluene, ether, tetrahydrofuran, dimethylsulfoxide, dimethylform-amide, dimethyl acetamide, hexamethyl phosphortriamide.
M-1076-Cl :~17~6~3 The reaction temperature varies from -120C to about 25C, a preferred reaction temperature being about -70C, with the reaction period ranging frvm about l/2 hour to 24 hours.
Removal of the protecting groups, as represented in the foregoing reaction scheme in the step relating to the conversion of compounds 6 to the compounds of Formula XI, is achieved by treatment of compounds 6 with an aqueous acid such as hydrochloric acid or toluene sulfonic acid.
Alternatively, an aqueous base such as sodium hydroxide or potassium hydroxide, or hydrazine or phenylhydrazine may be employed.
The propargylamine derivatives of compounds 4 wherein Rlo is hydrogen are prepared by the addition of protecting groups on the acetylene function and the nitrogen function of propargylamine. Protection of the nitrogen function of the propargylamine is accomplished by forming a Schiff's base with a nonenolizable carbonyl bearing compound such as benzaldehyde, 2,2-dimethylpropanal or 2,2-diethylbutanal.
Protection of the acetylenic function is accomplished by reacting the above-described Schiff's base with a tri-alkylsilyl chloride wherein the alkyl moiety has from l to 4 carbon atoms and is either straight or branched.
Trialkylsilyl chlorides that can be utilized include trimethylsilylchloride or triethylsilylchloride.
The propargylamine derivatives of compounds 4, wherein Rlo is methoxy or ethoxy are prepared by reacting propar-gylamine wherein the acetylene function is protected by a trialkylsilyl group with benzoyl chloride, pivalic acid chloride, or 2,2-diethylbutyric acid chloride at 0C in a suitable solvent. Suitable solvents include diethyl ether, dioxane, tetrahydrofuran, chloroform, methylenechloride, dimethylformamide, dimethylacetamide, or chlorobenzene.
The reaction is conducted in the presence of an organic base such as triethylamine or pyridine after which the reaction mixture is allowed to warm to about 25C for .
M-1076-Cl 6~3 one hour. The resulting amide derivative is combined with an alkylating reagent, such as, methylfluorosulfonate, dimethylsulfate, methyliodide, methyl p-toluenesulfonate or trimethyloxonium hexafluorophosphate when Rlo is methoxy, or triethyloxonium tetrafluoroborate when Rlo is ethoxy, at about 25C in a chlorinated hydrocarbon solvent such as methylene chloride, chlorobenzene or chloroform.
The reaction mixture is refluxed for about 12 to 20 hours, cooled to about 25C and an organic base such as triethyl-amine or pyridine is added. The resulting solution isextracted with brine and the desired product isolated therefrom.
The protected propargylamine starting material is obtained by treating a 3-trialkylsilylprop-2-ynyl-1-imino-benzyl derivative, that is compounds 4 wherein Rlo ishydrogen and Rll is phenyl, with hydrazine or phenylhydra-zine at about 25C for about 1/2 hour after which the mixture is diluted with, for example, petroleum ether, benzene or toluene and the amine isolated. Alternatively, the imine is hydrolyzed with 0.5 to 1 N HCl solution, an~
the aqueous phase evaporated to afford the amine as the hydrochloride salt.
Compounds of formula I wherein Z is H2N-CH(CH2)2;
Y is CH2F or CHF2; and Rl is hydrogen are prepared by reducing a ketone of the formula o Z '--C--Y
(XII) ,R13 R113 wherein Z' is phthaloyl-NCH(CH2)2-, benzoyl-NHCH(CH2)2-, - M-1076-Cl ~17~3 R,13 R,13 alkanoyl-NHCH(CH2)2-, alkoxycarbonyl-NHCH(CH2)2- or R,l~
benzyloxycarbonyl-NHCH(CH2)2- wherein the alkanoyl moiety has from 2 to 5 carbon atoms and is straight or branched, the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched, Y is CH2F and CHF2 and R13 is methyl.
The ketones are reduced to the corresponding alcohol which is treated with one equivalent of an imide, such as, phthalimide, succinimide or maleimide, 1.1 equivalents of a phosphine, for example, triphenylphosphine or a trialkylphosphine, such as, tri-n-butylphosphine and 1.1 equivalents of diethyl azodicarboxylate in a suitable solvent. Suitable solvents include ethers such as diethyl ether, tetrahydrofuran or ~-dioxane, benzene or dimethoxy-ethane. The reaction is conducted at about 0 to 100C, preferably about 25C, for a period of about one-half hour to 24 hours under an inert atmosphere such as nitrogen or argon. The thus obtained imido derivative is then hydrolyzed to the free amine.
The compounds of general formula (XII) wherein Y is FCH2- are prepared by treating a compound of the formula R
z ' -C-CH2R14 (XIII) wherein Z' is defined as above and R14 is a suitable leaving group, such as chlorine, bromine or iodine, mesylate, tosylate, triflate or trifluoroacetate with an appropriate fluorinating reagent, such as, potassium fluoride, silver fluoride, cesium fluoride, thallium fluoride, tetrabutylammonium fluoride in a suitable solvent. Suitable solvents include solvents such as M-1076-Cl 3L174~;Q3 dimethoxyethane, dimethylsulfoxide, dimethylformamide, ethylene glycol, acetonitrile, acetone, benzene or hydrogen fluoride. The reaction is conducted at a temperature of from about 0 to 200C for a period of about 2 to 48 hours.
The leaving group Rl4 may also be a diazo group in which case the fluorinating reagent employed is hydrogen fluor-ide/pyridine. Suitable solvents for the reaction wherein R14 is a diazo group are aprotic solvents such as diethyl ether, tetrahydrofuran and pentane. The reaction time varies from about 30 minutes to 24 hours at a temperature ranging from about -20 to 65C. Illustratively, a com-pound of the formula o Z '-C-R14 as defined above wherein Rl4 is a diazo group in a suitable aprotic solvent is added to a solution of hydrogen fluor-ide/pyridine and cooled to -10C. The reaction mixture is stirred vigorously at -10C for l hour, warmed to about 25C for 2 hours and then poured over ice. The organic phase is separated, washed with a base such as sodium bicarbonate, dried over magnesium sulate and concentrated under vacuum to afford the appropriate fluoromethyl ketone derivative of formula (XII).
The diazo ketone derivatives, that is, the compounds of formula (XIII) wherein R14 is a diazo group, can be obtained via the corresponding acid halide represented by a compound of the formula o Z'-C-halide wherein halide may be, for example, chloride and Z' has the meaning defined in formula (XII). The acid halide contained in an aprotic solvent, as for example diethyl ether, tetrahydrofuran, pentane, hexane, benzene, dimeth-oxyethane or dioxane, is added to a solution of diazo-methane in ether cooled to about -~0 to 20C, followed M-1076-Cl -21- 1174~3 by vigorous stirring at about 25C for about l to 24 hours. The diazo ketone derivative so obtained can be isolated using standard procedures such as evaporation of the solvent with subsequent purification by recrystallization or chromatography. ~lternatively, the reaction mixture can be treated with an appropriate fluorinating reagent as described above without isolation.
The appropriately substituted diazo ketone derivative described above can be used to prepare compounds of formula (XIII) wherein R14 is, for example, halogen, mesylate, tosylate, triflate, or trifluoroacetate using procedures generally known to the art. To obtain compounds of general formula (XIII) wherein R14 is halogen, such as, chlorine, bromine, or iodine the corresponding compound of formula (XIII) in which Rl4 is a diazo group is treated with either aqueous hydrogen chloride, hydrogen bromide or hydrogen iodide in a suitable aprotic solvent. In order to obtain compounds of formula (XIII) wherein Rl4 is mesylate, tosylate, triflate or trifluoroacetate, the corresponding diazo ketone derivative, wherein R14 is a diazo group is dissolved in a suitable aprotic solvent and treated with dilute sulfuric acid to yield the corresponding benzyl methanol ketone derivative. Lastly, the benzyl methanol ketone is esterified with an appropriate acid chloride or acid anhydride utlizing methane sulfonic acid, p-toluene sulfonic acid, tri-fluoromethyl sulfonic acid or trifluoroacetic acid.
The acid halides, that is, compounds of the formula o Z'-C-halide as described above, are known compounds which can be pre-pared from the corresponding acids. Thus, for example, M-1076-Cl ~'7~ 33 treatment of the appropriate acid with thionyl chloride in an aprotic solvent, such as, diethyl ether, tetra-hydrofuran, benzene or dichloromethane at a temperature ranging from about 0C to the reflux temperature of the solvent for about 1 to 24 hours results in the foundation of the corresponding acid halide. Alternatively, treat-ment of the appropriate acid with oxalyl chloride in one of the aprotic solvents described above at a temperature of about 0 to 40C for about 1 to 24 hours also results in the preparation of the corresponding acid halide.
The compounds of general formula (XII) wherein Y
Rl is FCH2- and Z' is other than benzoyl-NHC(CH2)2- or ,Rl alkanoyl-NHC(CH2)2- may also be obtained by treating a compound of the formula z2-Rl5 (XIV) R,13 wherein Z2 is phthaloyl-N-CH(CH2)2-, alkoxycarbonyl-R,13 R,13NHC(CH2)2-, benzyloxycarbonyl-NHC(CH2)2-, ~-methylthioethyl or ~-benzylthioethyl; R13 is methyl; and Rls is chlorine, bromine or iodine, mesylate or tosylate. Thus, a compound of formula (XIV) is reacted with triphenylphosphine or tri-(lower)-alkylphosphine, for example, tri-n-butyl-phosphine, in a solvent such as benzene, toluene, methanol, ethanol, acetonitrile, tetrahydrofuran, diethyl ether or dimethoxyethane. The reaction is conducted at a temperature ranging from 25C to the reflux temperature of the solvent M-1076-Cl for ajperiod ranging from about 10 minutes to 48 hours.
On cooling the precipitate which forms is washed with solvent and recrystallized to give the appropriate phos-phonium salt. The triphenylphosphonium or trialkylphos-phonium salt is added to an excess (up to 25%) of sodiumor lithium metal dissolved in liquid ammonia to which a catalytic amount of ferric nitrate is added. Stirring is continued for about 10 minutes to 3 hours after which the ammonia is evaporated under an inert atmosphere, such as, nitrogen or argon. An appropriate solvent, such as, benzene, toluene, diethyl ether, tetrahydrofuran or di-methoxyethane is added and the resulting substituted methylidenephosphorane is collected. The methylidene-phosphorane is treated with a lower alkyl ester of mono-fluoroacetic acid in a solvent such as benzene, toluene,diethyl ether, tetrahydrofuran or dimethoxyethane. The reaction is conducted under an inert atmosphere such as nitrogen or argon at a temperature ranging from about 0C
to the reflux temperature of the solvent for a period of from about 30 minutes to 24 hours. The reaction mixture is concentrated by distillation to yield an olefin. The olefin is treated with an aqueous mineral acid, such as hydrochloric or hydrobromic acid or an organic acid such as trifluoroacetic acid or ~-toluene sulfonic acid in the presence of a cosolvent such as tetrahydrofuran, diethyl ether, or benzene for a period of from about 30 minutes to 24 hours at a temperature ranging from about 0C to the reflux temperature of the solvent. The amount of acid employed may vary from a catalytic amount to a concentrated acid solution.
As used in general formula (XIV) the term phthaloyl-N-CH(CH2)2- is taken to mean the group o C Rl 3 ~-~ M-1076-Cl
4~3 the term alkoxycarbonyl-NHCH(CH2)2- is taken to mean the group alkyl-O-C-NHCH(CH2)2-, the term benzyloxycar-R13bonyl-NHCH(C~2)2- is taken to mean the group ~ -CH2-O ,Rl 3 OCNHCH(CH2)2-, wherein R13 has the meanings defined in formula (XIV) and alkyl is a straight or branched group having from 1 to 4 carbon atoms.
Compounds of general formula (XII) wherein Y is F2CH- are obtained by treating ~[(methylsulfinyl)methyll-- thio]methane or [[(ethylsulfinyl)methyl]thio]ethane with a suitable strong base followed by alkylation with an appropriate derivative of the formula Z '-R16 (XV) wherein in formula (XV) the symbol Z' has the meaning previously defined in formula (XII) and R16 is chlorine, bromine, iodine, mesylate or tosylate. The thus formed Z' substituted sulfinyl derivative is treated with a suitable strong base followed by alkylation using an appropriate halomethylhalo alkylating reagent selected from chlorodifluoromethane, bromodifluoromethane, and difluoriodomethane. The alkylation reaction is followed by a hydrolysis using an aqueous acid solution.
Suitable strong bases which may be employed in preparing the difluoromethyl substituted ketone derivatives as described above are sodium hydride, dilithium acetylide, lithium diisopropylamide, butyllithium, potassium tert-butoxider sodium tert-butoxide, lithium tert-butoxide, phenyllithium, methyllithium, sodium amide, lithium amide or potassium hydride.
~7a~6~3 The alkylation reaction described in preparing the difluoromethyl ketone derivatives are carried out in an appropriate solvent, for example, tetrahydrofuran, di-ethyl ether, hexamethylphosphortriamide, dimethylsul-foxide, or benzene. The reaction is conducted at atemperature ranging from about -78 to 65C for a period of from about 30 minutes to 24 hours. Preferably, a temperature of about 40C is utilized for the difluoro-methyl alkylation step. The alkylated sulfinyl inter-mediates are isolated by quenching with a brine solutionfollowed by extraction utilizing diethyl ether, dichloro-methane, or benzene. The alkylated sulfinyl intermediates are recovered from the combined extracts.
Hydrolysis of the alkylated sulfinyl derivatives to the ketone is achieved using an aqueous mineral acid solution, such as, hydrochloric, hydrobromic, perchloric or sulfuric acids in a solvent such as tetrahydrofuran, acetonitrile, diethyl ether or benzene. The hydrolysis is conducted at a temperature ranging from about -20 to 105C, preferably about 25C for a period of from about 30 minutes to 24 hours, preferably about 2 hours. Generally, a solution of 0.3 equivalents of mineral acid in 1.5~
water is employed. The specific examples described below further illustrate the preparation of the difluoromethyl ketone derivatives of formula (XII).
The compounds of formulas (XIV) and (XV) wherein R15 and R16 are halogen are known to the art or can be pre-pared from an appropriate carboxylic acid derivative having the formula Z4-COO~
(XVI) -- M-1076-Cl wherein Z4 is phthaloyl-NCH(CH2)-, benzoyl-NHCH(CH2)-, R,13 R113 alkanoyl-NHCH(CH2)-, alkoxycarbonyl-N~CH(CH2)-, benzyloxycarbonyl-NHCH(CH2)-, methylthiomethyl or benzylthiomethyl. These acids are known to the art or can be obtained by known procedures from the corresponding unprotected amino acids~ The compounds of formulas (XIV) and (XV) wherein Rls and R16 are mesylate or tosylate may be prepared by treating the corresponding derivatives in which Rls and R16 are halogen with a metal salt of methanesulfonic acid or ~-toluenesulfonic acid. Illustra-tively, the sodium salt of methanesulfonic acid or ~-toluenesulfonic acid can be utilized.
Reduction of the ketones of formula (XII) to the corresponding alcohols is achieved chemically using 1 to 10 equivalents of a metal hydride, such as lithium boro-hydride, sodium borohydride, sodium cyanoborohydride, or lithium aluminum hydride. In addition the ketones can be reduced with borane or dimethylthioborane or catalytically reduced using, for example, Raney nickel, rhodium, palladium on charcoal, or platinum oxide. In general, the reaction time varies from about 10 minutes to 24 hours and the temperature at which the reduction is conducted can range from about -40C to 100C depending upon the particular reducing reagent employed. When hydride or borane re-duction is employed the reaction is conducted in a suitablesolvent for a period of time from about 10 minutes to 24 hours with temperatures ranging from about -40C to 65C.
Suitable solvents that can be employed for reduction of compounds of general formula (XII) include lower alcohols, such as methanol or ethanol, or ethers, such a.s diethyl ether or tetrahydrofuran. When catalytic reduction is .~
~ M-1076-Cl ~:7~6~;~
employed the reaction time varies from about 1 hour to 24 hours, the reaction temperature ranges from about 25 to 100C and the hydrogen pressure can range from 1 to 120 atmospheres.
Hydrolysis to the amine and the removal of any distal amine protecting group is achieved using a strong mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as toluenesulfonic acid or trifluoroacetic acid. The hydrolysis is conducted in water or an aqueous solvent at the reflux temperature for a period of from about 4 to 48 hours. Alternatively, 1 to 3 equivalents of hydrazine, methylhydrazine or methylamine can be utilized at a temperature of from about 25C to the reflux temperature of the solution for about 1 to 12 hours, followed by treatment with a strong mineral acid or organic acid as described above.
Compounds of formula I wherein Z is H2N-CH(CH2)2;
Rl is hydroxy; and Y is C CH, or as hereinafter indicated the alkynyl group, are prepared by the hydrolysis of the alkylated compounds 5, described above. The desired alkylating reagents RgX that are employed can be prepared by methods known to the art. Thus, the reagent PhHc=NcH2(cH2)2-can be prepared by reacting 3-bromo-n-propylamine hydrochloride with benzaldehyde and an organic trialkyl-amine, such as triethylamine, in a solvent such as diethyl ether, tetrahydrofuran, dioxane, chloroform or dichloro-methane. The reactant C,H3 PhHC=~CH(CH2)2-is prepared by reacting 3-aminobutylbromide hydrobromide with benzaldehyde and an organic amine such as triethyl-amine. The compound 3-aminobutylbromide hydrobromide is M-1076-Cl ~L17~6~3 a known compound that can be prepared from the corres-ponding alkanol by treatment with concentrated HBr at a temperature of from 25C to 110C for a period of from 1 to 12 hours. The ~-aminoalkanol derivative is obtained by treating an appropriate ~-keto-alkanoic acid ester the formula 0, 0 CH3C-CH2C-OcH2cH3 The ~-keto-alkanoic acid ester is treated with hydroxylamine to form the corresponding oxime, which is reduced with lithium aluminum hydride in ether or tetrahydrofuran at a temperature of from 25 to 50C
for a period ranging from 1 to 12 hours. Subsequent hydrolysis of the ester moiety results in the formation ~f the y-aminoalkanol.
The alkylating reactic,n may be carried out in an aprotic solvent, for example, benzene, toluene, ether, tetrahydrofuran, dimethylsulfoxide or hexamethyl phos-phortriamide. The reaction temperature varies from about -100 to 25C preferably about -70C and the reaction 2~ time varies from about 1/2 hour to 24 hours.
Removal of the protecting groups, as represented in the reaction scheme in the step going from compounds 5 to the desired amines, is achieved by treatment with aqueous acid, for exaple, hydrochloric acid followed by aqueous base, for example, sodium hydroxide or potassium or treat-ment with phenylhydrazine, hydroxylamine or hydrazine then with aqueous base.
The individual optical isomers of compounds of formula I wherein Rl is carboxy or hydrogen are resolved using a (+) or (-) binaphthylphosphoric acid salt in accordance with the procedure of R. Viterbo et al., Tetrahedron Letters 48, 4617 (1971). Other resolving agents such as ~+) camphor-10-sulfonic acid may also be employed. Alternatively, when Z is H2~-rH-(CH2)2 or M-1076-Cl 117~6~3 H2N(CH2)n, resolution is achieved via the lactam of said compounds. The thus resolved acids and amines ~ay be employed in the same manner as described hereinabove for the racemic mixtures.
The compounds described herein are useful in in-hibiting the growth of protozoa in animals. The term "animals" is intended to include inter alia mammals, such as mice, rats, guinea pigs, rabbits, ferrets, dogs, cats, cows, horses and primates including man. Also encom-passed within the term animals are both fish and fowl.
The term "fowl" is intended to include male or female birds of any kind including parrots and canaries, but is primarily intended to encompass poultry which are commercially raised for eggs or meat. Accordingly, the term "fowl" is particularly intended to encompass hens, cocks and drakes of chickens, turkeys and ducks.
The term "protozoa" is intended to include those members of the subphyla Sarcomastigophora and Sprozoa of the phylum Protozoa. More particularly, the term "protozoa" as used herein is intended to include those genera of parasitic protozoa which are important to man because they either cause disease in man or his domestic animals. These genera are for the most part found classified in the superclass of Mastigophora of the subphylum Sarcomastigophora and the class of Telosporea of the subphylum Sporozoa in the classification according to Baker (1969). Illustrative genera of these parasitic protozoa include Histomonas, Trypanosoma, Giardia, Trichomonas, Eimeria, Isopora, Toxoplasma and Plasmodium.
3~ Excluded from the superclass of Mastigophora is the genus Leishmania, certain species of which cause the tropical disease of Leishmaniasis in man. Also, specifi-cally excluded from the genus Trypanosoma, as used in this invention, are the species Trypanosoma cruzi, which can cause Chagas' disease in man, and the species M-1~76-Cl :11746~3 Trypanosoma lewisi. The compounds described herein have been found not to be particularly effective against these species.
On the other hand, the compounds of Formula I are particularly useful in inhibiting the growth of Trypanosoma brucei, the causative agent for nagana, or the tsetse-fly disease of horses and cattle in central Africa. The compounds described herein are also re-markably effective in inhibiting the growth of Eimeria tenella, a species of protozoa causing coccidiosis in fowl.
Indeed, a preferred embodiment of the present invention is the use of these compounds to inhibit the growth of intestinal coccidia in commercial poultry.
The economic importance of intestinal coccidia is highly significant. Thus in 1972, the estimated loss to the poultry industry in the United States due to coccidial infections was approximately 47 million dollars. Due to the rapid development of drug resistance by coccidia, and due to the relatively high toxicity of some of the drugs used in the treatment of coccidiosis, there is a need for effective coccidiostats that are non-toxic and to which intestinal coccidia do not develop rapid drug resistance.
It is not exactly understood how the compounds of this invention are able to inhibit the growth of protozoa.
Inter alia, the compounds described herein are irreversi-ble inhibitors of ornithine decarboxylase and S-adenoxylmethionine decarboxylase. As irreversible inhibitors of these enzymes, these compounds inhibit polyamine formation which may be required for protozoal cell division. In any event, the practice of this invention is not limited to any particular mode or theory of action whereby the compounds of this invention are able to effectively inhibit the growth of protozoa.
M-1076-Cl :a~746~3 The effect of the compounds of general for~ula (I) upon the growth of protozoa, and more particularly upon the growth of coccidia, can be demonstrated using Eimeria tenella and two week old male white leghorn chicks as the test animals. The birds are kept in batteries and both the infected and non-infected birds are housed in separate rooms to assure the maintenance of coccidia-free birds.
Each experimentally infected bird receives lO0,000 sporylated oocysts via gavage. The test compound is administered in the particular dosage desired through the drinking water and drug-free mash is provided ad libitum.
To evaluate the effect of the active ingredient on E
tenella infections, the chicks are sacrificed with carbon dioxide, necropsied, generally at day five of the study, and cecal lesions evaluated.
The inhibition of protozoal growth can also be determined using Trypanosoma brucei brucei, which is the causative agent of bovine trypanosomiasis (nagana) in Africa. The related species Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense are the causative agents for African sleeping sickness in humans.
In general, drug activity is tested against established infections of a pleomorphic EATRO 110 isolate of T. b.
brucei in mice. Test animals are infected with 5 x 105 parasites twenty four hours prior to testing. Control animals so infected generally die 5 days subsequent to innoculation. The compound to be tested is ad~inistered to the test animals via their drinking water in varying dosages. Animals cured of the infection remain parasite-free more than 30 days after the deaths of the controlanimals as indicated by an examina~ion of blood smears.
The compounds described herein are employed in M-1076-Cl amounts that are effective in inhibiting protozoal growth.
These amounts will depend, of course, upon various factors, such as the type and nature of the protozoal infection, the activity of the specific compound, the age, sex and species of animal treated and whether the treatment is prophylactic or therapeutic. In general, the compounds described herein can be orally or parenterally administered at a daily dose ranging from 5 mg/kg to 7 g/kg. Preferably, in the case of Trypanosoma infections the dosage range is from about 600 mg/kg to about 2 g/kg. In the case of Eimeria in-fections the dose can be lowered, ranging from about 15 mg/kg to about 1 g/kg.
Due to the low toxicity of the compounds described herein, the compounds can be safely administered ad libitum via the drinking water of the test animals in the treatment of coccidiosis in fowl. Generally speaking, concentrations of the active ingredient ranging from about 0.01% to about 2~ are suitable, depending primarily upon the nature of the protozoal infection to be treated whether prophylactic or therapeutic, the severity of the infection and the period of treatment.
Thus, for example the compound 2-difluoromethyl-2,5-diaminopentanoic acid can be effectively administered to chickens for the treatment of coccidiosis one day prior to infection as a 2% solution. Alternatively, a prophylactic course of treatment can be utilized 8 days prior to in-fection utilizing concentrations of 2-difluoromethyl-2,5-diaminopentanoic acid as low as 0.015~ in the drinking water of chickens. Preferably, a prophylactic concentra-tion of from 0.06% to about 1.0% is preferred.
This prophylactic treatment for the inhibition of protozoal growth provides one of the principle advantages to the use of the decarboxylase inhibitors described herein.
Thus, in the case of coccidia infections in chickens, for example, Eimeria tenella grows intracellularly in M-1076-Cl 4~;~3 the epithelial cells of the caecum as a trophozoite stage. Subsequently, these cells undergo a form of multiple mitosis to form a large number of merozoites.
These merozoites are released as the host cell lyses and serve to extensively infect fresh cells. The result is that the wall of the caecum is badly damaged, leading to severe blood and fluid loss and finally death. More-over, during the life cycle of E. tenella, resistant oocysts are produced which are voided in the faeces of chickens. Chickens being coprophagous in nature, the disease is rapidly spread by contamination of their food supply. Accordingly, coccidial infections in commercial flocks, when they occur, are epidemically treated with massive doses of currently available chemotherapeutic agents, that are primarily cidal in nature. Consequently, medicated feeds are now routinely employed in commercial flocks, so that all commercial fowl now receive almost constant medication to prevent outbreaks of coccidiosis from occurring.
The fact that the decarboxylase inhibitors herein described can be prophylactically administered, enables the host to overcome either a subsequent natural or artificial induced infection enzymatically via an inhi-bitory mechanism rather than via a cidal action. Thus, in the case of an E. tenella infection, the infection is curtailed in a manner that enables the host to avail itself of its own body defense mechanisms. The resulting antibodies which are produced via such a controlled infection, serve to further permanently immunize the host from future E. tenella infections.
The pharmaceutical compositions that are particularly suited for the prophylaxis or treatment of protozoal infec-tions in fowl comprise the heretofore described ~-substituted-amines or the ~-substituted-~-amino acids in combination M-1076-Cl ~1'74~ 3 with a pharmaceutically acceptable carrier. Advantageously, the antiprotozoal compositions are prepared by admixing the active compound with an inert carrier material. Typical carriers include talc, clay, pumice, silica, chalk, diatomaceous earth, walnut shell flour and equivalents thereof. Alternatively, the active ingredient can be admixed with a commercial feedstuff or vitamin and mineral pre-mix particularly adapted for fowl.
In most cases a concentrated aqueous solution of the active ingredient is employed in the management and treat-ment of coccidiosis in fowl. The compounds described, for the most part, are highly soluble, particularly in the form of their salts. Such solutions may advantageously contain preservatives, such as parabens, benzyl alcohol, phenol or thimerosal. In addition, isotonic agents, sugars, stabilizing or buffering agents can be usefully employed.
The compounds of formula (I) can be used in conjunction with other known drugs currently in use for the chemotherapy and chemoprophylaxis of disease caused by parasitic protozoa.
Generally, this has the effect of decreasing the amount of enzyme inhibitors administered. Such drugs include, among others: Antrycide, quinapyramine; Berenil, Diminazene aceturate; Pentamidine isethionate; Primaquine; Tryparsamide;
Amicarbalide; Amprolium; Amphotericin B; quinine; ~onensin;
Minocycline, 7-dimethylamino-6-demethyl-6-deoxytetracycline;
Clindamycin, 7-deoxy-7(S)-chlorolincomycin; Buquinolate;
Robenidine; and Nicarbazin. In some instances the compounds of formula (I) actually enhance or potentiate the effects of these drugs.
Of particular interest in this regard is the compound 2,5-diamino-2-difluoromethylpentanoic acid which has been shown to act synergistically with the antiprotozoal agents Antrycide, quinapyramine, Pentamidine isethionate and M-1076-Cl :~17~6~3 Amicarbalide. Thus, the 2,5-diamino-2-difluoromethyl-pentanoic acid concentration can be reduced by about four-fold when used in combination with subcurative doses (less than 1.0 mg/kg) of these drugs.
Additionally, the compounds of formula (I) can be used in combination with other known cytotoxic agents for the chemotherapy and chemoprophylaxis of parasitic diseases, particularly trypanosomiasis. Such cytotoxic agents include the antineoplastic antibiotic Bleomycin as well as other well-known cytotoxic agents, as for example, cyclophosphamide, methotrexate, prednisone, 6-mercaptopurine, procarbozine, daunorubicin, vincristine, vindesine, vinblastine, chlorambucil, cytosine arabinoside, 6-thioguanine, thio TEPA, 5-fluorouracil, 5-fluoro-2-deoxyuridine, 5-azacytidine, nitrogen mustard, 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU), busulfan or adriamycin.
Of particular interest in the treatment of trypanoso-miasis in general, and more particularly in the treatment of nagana in cattle, is the use of the enzyme inhibitor 2,5-diamino-2-difluoromethylpentanoic acid in combination with the antitumor antibiotic Bleomycin. This particular enzyme inhibitor appears to act synergistically with Bleomycin. Thus, mice infected with Trypanosoma brucei are cured after three days upon daily i.p. administration of Bleomycin at a dosage of 7 mg/kg. Similarly, trypanosome infections in mice are cured by the adminis-tration of a 1% solution of 2,5-diamino-2-difluoromethyl-pentanoic acid in the drinking water for 3 days.
The results of several combination experiments indicate that cures are consistently effected with 0.5 mg/kg of Bleomycin in combination with 0.5~ of 2,5-diamino-2-difluoromethylpentanoic acid administered via drinking water. Alternatively, cures are effected with concentrations M-1076-Cl ~7~6~3 of 0.25 mg/kg of Bleomycin in combination with only 0.25%
of 2,5-diamino-2-difluoromethylpentanoic acid in the drinking water. A combination of 0.1 mg/kg of Bleomycin and 0.1% of 2,5-diamino-2-difluoromethylpentanoic acid has no effect. Thus, the curative dosage combinations reflect a reduction in Bleomycin drug dosage of from 1/2 to 1/28 of the curative dose of the drug used singly, when used in combination with a subcurative dose of from 1/2 to 1/4 of the curative dose of 2,5-diamino-2-difluoromethylpentanoic acid.
The invention described and claimed herein is moreparticularly illustrated in conjunction with the following Examples specifically describing how the compounds of this invention can be prepared and utilized.
2-Difluoromethyl-2,5-diaminopentanoic acid Under nitrogen a solution (500 ml) of 2M butyl-lithium in hexane is added to a stirred solution of 143.1 ml of diisopropylamine in l.S liters of tetrahydrofuran at -78C after which 261 g (0.81 mole) of ornithine di-benzaldimine methyl ester in 1.5 liters of tetrahydrofuran is added. Upon completion of the addition the reaction temperature is raised to 40C and maintained between 40 and 50C for 3 hours during which time chlorodifluoro-methane gas is bubbled through the mixture with stirring.
The reaction mixture is then treated with a saturated solution of sodium chloride. The organic material is extracted with ether, and the ether extract washed several times with sodium chloride solution, dried over magnesium sulfate and evaporated to give a viscous oil.
The oil is stirred with lN HCl (1.5 1) for 3 hours, the mixture extracted several times with chloroform and the aqueous solution evapo.ated to dryness. The oily residue is refluxed with 12N hydrochloric acid (1.5 1) M-1076-Cl ~7a~6!r~3 for 16 hours, the cooled solution clarified by chloro-form extraction before concentration, decolorization (charcoal), and further concentration to about 750 ml.
The pH of the solution i5 adjusted to 3.5 by the 2ddition S of triethylamine, the ~olution treated again with char-coal before concentration to about 5û0 ml and dilution with 7-8 liters of acetone. The precipitated product is filtered off and washed with ethanol. The crude product is recrystallized by dissolving in about 150 ml hot 10 water and treatment of the solution with hot ethanol (450 ml). On cooling crystals of 2-difluoromethyl-2,5-diaminopentanoic acid hydrochloride monohydrate separaLe 71 g (37%), m.p. 183C.
lS ~-Ethynyl-~,~-diaminovaleric acid 11.~ g (0.048 M) of N-(3-trimethylsilylprop-2-ynyl)-. .
benzenecarboximidate in 20 ml of tetrahydrofuran is added to lithium diisopropylamide, prepared from 4.9 g (6.78 ml, 0.048 M) of diisopropylamide in 60 ml of tetrahydrofuran 20 and 23.6 ml of 2.05 M solution of n-butyllithium at -70C
after which 9.5 g (0.042 M) of N-(3-bromopropyl)benzylimine is added, and the mixture is stirred at -70C for 5-1/2 hours. To the reaction mixture is added 23.6 ml of a 2.05 M solution of n-butyllithium followed by the addition 25 of 4 5 g (3.67 ml, 0.048 M) of methyl chloroformate.
After 30 minutes at -78C the mixture is treated with brine, and the reaction product ls isolated by ether extraction. The ether extract is e~aporated and 300 ml of 3 N HCl is added to the resulting residue and the 30 mixture is refluxed for 7 hours. On cooling the mixture is washed well with methylene chloride, made alkaline and washed again. The aqueous solution is acidified and concentrated to dryne ,s. The residue is triturated with ethanol, filtered and the ethanol ~vaporated. The residue ` 11746~3 M-1076-Cl is dissolved in water, the pH adjusted to 6, and the solution is applied to a column of Amberlite 120 H+, eluting with 1 M NH40H which affords, upon recrystalliza-tion from ethanol-water, ~-ethynyl-~, ~-diaminovaleric acid, M.P. 168-169 (dec.).
In the above procedure N-(3-bromopropyl)benzylimine is prepared from 3-bromopropylamine and benzaldehyde by procedures generally known in the art.
1-Fluorometh 1-1 4-butanediamine dihvdrochloride Y
To a solution of 40 mmole of diazomethane in 110 ml of ether cooled to 0C and magnetically stirred is added under nitrogen dropwise over a period of 1 hour a solution of 20 ml of 4-phthalimidobutyryl chloride in 75 ml of ether. Stirring is continued for 1 hour at 25C after which the reaction mixture is added to a solution of 40 ml of HF/pyridine precooled to 0C. The resulting heterogeneous mixture is stirred at 25C for 1-1/2 hours and then poured on ice water. The ether phase is separated, washed with a solution of bicarbonate, then with brine and dried over magnesium sulfate. Concentra-tion of the solvent under reduced pressure affords a solid which is recrystallized from diethylether/pentane to give fluoromethyl 3-phthalimidopropyl ketone, m.p.
92C.
To a solution of 550 mg (2.2 mmole) of fluoromethyl 3-phthalimidopropyl ketone in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol cooled to -20C is added a solution of 0.8 mmole of sodium borohydride in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol precooled to -20C. The reaction mixture is stirred for 15 minutes at -20C and then neutralized with 2 M ~Cl to a pH of 1. The solvents are evaporated under reduced pressure and the residue is partitioned between water * Trade Mark ~ ~746~3 M-1076-Cl and chloroform. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give a residue which is recrystallized from tetrahydrofuran-diethylether to afford l-fluoro-5-phtllalimido-2-pentanol, m.p. 85C. A mixture of 264 mg (1.05 mmole) of l-fluoro-
Compounds of general formula (XII) wherein Y is F2CH- are obtained by treating ~[(methylsulfinyl)methyll-- thio]methane or [[(ethylsulfinyl)methyl]thio]ethane with a suitable strong base followed by alkylation with an appropriate derivative of the formula Z '-R16 (XV) wherein in formula (XV) the symbol Z' has the meaning previously defined in formula (XII) and R16 is chlorine, bromine, iodine, mesylate or tosylate. The thus formed Z' substituted sulfinyl derivative is treated with a suitable strong base followed by alkylation using an appropriate halomethylhalo alkylating reagent selected from chlorodifluoromethane, bromodifluoromethane, and difluoriodomethane. The alkylation reaction is followed by a hydrolysis using an aqueous acid solution.
Suitable strong bases which may be employed in preparing the difluoromethyl substituted ketone derivatives as described above are sodium hydride, dilithium acetylide, lithium diisopropylamide, butyllithium, potassium tert-butoxider sodium tert-butoxide, lithium tert-butoxide, phenyllithium, methyllithium, sodium amide, lithium amide or potassium hydride.
~7a~6~3 The alkylation reaction described in preparing the difluoromethyl ketone derivatives are carried out in an appropriate solvent, for example, tetrahydrofuran, di-ethyl ether, hexamethylphosphortriamide, dimethylsul-foxide, or benzene. The reaction is conducted at atemperature ranging from about -78 to 65C for a period of from about 30 minutes to 24 hours. Preferably, a temperature of about 40C is utilized for the difluoro-methyl alkylation step. The alkylated sulfinyl inter-mediates are isolated by quenching with a brine solutionfollowed by extraction utilizing diethyl ether, dichloro-methane, or benzene. The alkylated sulfinyl intermediates are recovered from the combined extracts.
Hydrolysis of the alkylated sulfinyl derivatives to the ketone is achieved using an aqueous mineral acid solution, such as, hydrochloric, hydrobromic, perchloric or sulfuric acids in a solvent such as tetrahydrofuran, acetonitrile, diethyl ether or benzene. The hydrolysis is conducted at a temperature ranging from about -20 to 105C, preferably about 25C for a period of from about 30 minutes to 24 hours, preferably about 2 hours. Generally, a solution of 0.3 equivalents of mineral acid in 1.5~
water is employed. The specific examples described below further illustrate the preparation of the difluoromethyl ketone derivatives of formula (XII).
The compounds of formulas (XIV) and (XV) wherein R15 and R16 are halogen are known to the art or can be pre-pared from an appropriate carboxylic acid derivative having the formula Z4-COO~
(XVI) -- M-1076-Cl wherein Z4 is phthaloyl-NCH(CH2)-, benzoyl-NHCH(CH2)-, R,13 R113 alkanoyl-NHCH(CH2)-, alkoxycarbonyl-N~CH(CH2)-, benzyloxycarbonyl-NHCH(CH2)-, methylthiomethyl or benzylthiomethyl. These acids are known to the art or can be obtained by known procedures from the corresponding unprotected amino acids~ The compounds of formulas (XIV) and (XV) wherein Rls and R16 are mesylate or tosylate may be prepared by treating the corresponding derivatives in which Rls and R16 are halogen with a metal salt of methanesulfonic acid or ~-toluenesulfonic acid. Illustra-tively, the sodium salt of methanesulfonic acid or ~-toluenesulfonic acid can be utilized.
Reduction of the ketones of formula (XII) to the corresponding alcohols is achieved chemically using 1 to 10 equivalents of a metal hydride, such as lithium boro-hydride, sodium borohydride, sodium cyanoborohydride, or lithium aluminum hydride. In addition the ketones can be reduced with borane or dimethylthioborane or catalytically reduced using, for example, Raney nickel, rhodium, palladium on charcoal, or platinum oxide. In general, the reaction time varies from about 10 minutes to 24 hours and the temperature at which the reduction is conducted can range from about -40C to 100C depending upon the particular reducing reagent employed. When hydride or borane re-duction is employed the reaction is conducted in a suitablesolvent for a period of time from about 10 minutes to 24 hours with temperatures ranging from about -40C to 65C.
Suitable solvents that can be employed for reduction of compounds of general formula (XII) include lower alcohols, such as methanol or ethanol, or ethers, such a.s diethyl ether or tetrahydrofuran. When catalytic reduction is .~
~ M-1076-Cl ~:7~6~;~
employed the reaction time varies from about 1 hour to 24 hours, the reaction temperature ranges from about 25 to 100C and the hydrogen pressure can range from 1 to 120 atmospheres.
Hydrolysis to the amine and the removal of any distal amine protecting group is achieved using a strong mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as toluenesulfonic acid or trifluoroacetic acid. The hydrolysis is conducted in water or an aqueous solvent at the reflux temperature for a period of from about 4 to 48 hours. Alternatively, 1 to 3 equivalents of hydrazine, methylhydrazine or methylamine can be utilized at a temperature of from about 25C to the reflux temperature of the solution for about 1 to 12 hours, followed by treatment with a strong mineral acid or organic acid as described above.
Compounds of formula I wherein Z is H2N-CH(CH2)2;
Rl is hydroxy; and Y is C CH, or as hereinafter indicated the alkynyl group, are prepared by the hydrolysis of the alkylated compounds 5, described above. The desired alkylating reagents RgX that are employed can be prepared by methods known to the art. Thus, the reagent PhHc=NcH2(cH2)2-can be prepared by reacting 3-bromo-n-propylamine hydrochloride with benzaldehyde and an organic trialkyl-amine, such as triethylamine, in a solvent such as diethyl ether, tetrahydrofuran, dioxane, chloroform or dichloro-methane. The reactant C,H3 PhHC=~CH(CH2)2-is prepared by reacting 3-aminobutylbromide hydrobromide with benzaldehyde and an organic amine such as triethyl-amine. The compound 3-aminobutylbromide hydrobromide is M-1076-Cl ~L17~6~3 a known compound that can be prepared from the corres-ponding alkanol by treatment with concentrated HBr at a temperature of from 25C to 110C for a period of from 1 to 12 hours. The ~-aminoalkanol derivative is obtained by treating an appropriate ~-keto-alkanoic acid ester the formula 0, 0 CH3C-CH2C-OcH2cH3 The ~-keto-alkanoic acid ester is treated with hydroxylamine to form the corresponding oxime, which is reduced with lithium aluminum hydride in ether or tetrahydrofuran at a temperature of from 25 to 50C
for a period ranging from 1 to 12 hours. Subsequent hydrolysis of the ester moiety results in the formation ~f the y-aminoalkanol.
The alkylating reactic,n may be carried out in an aprotic solvent, for example, benzene, toluene, ether, tetrahydrofuran, dimethylsulfoxide or hexamethyl phos-phortriamide. The reaction temperature varies from about -100 to 25C preferably about -70C and the reaction 2~ time varies from about 1/2 hour to 24 hours.
Removal of the protecting groups, as represented in the reaction scheme in the step going from compounds 5 to the desired amines, is achieved by treatment with aqueous acid, for exaple, hydrochloric acid followed by aqueous base, for example, sodium hydroxide or potassium or treat-ment with phenylhydrazine, hydroxylamine or hydrazine then with aqueous base.
The individual optical isomers of compounds of formula I wherein Rl is carboxy or hydrogen are resolved using a (+) or (-) binaphthylphosphoric acid salt in accordance with the procedure of R. Viterbo et al., Tetrahedron Letters 48, 4617 (1971). Other resolving agents such as ~+) camphor-10-sulfonic acid may also be employed. Alternatively, when Z is H2~-rH-(CH2)2 or M-1076-Cl 117~6~3 H2N(CH2)n, resolution is achieved via the lactam of said compounds. The thus resolved acids and amines ~ay be employed in the same manner as described hereinabove for the racemic mixtures.
The compounds described herein are useful in in-hibiting the growth of protozoa in animals. The term "animals" is intended to include inter alia mammals, such as mice, rats, guinea pigs, rabbits, ferrets, dogs, cats, cows, horses and primates including man. Also encom-passed within the term animals are both fish and fowl.
The term "fowl" is intended to include male or female birds of any kind including parrots and canaries, but is primarily intended to encompass poultry which are commercially raised for eggs or meat. Accordingly, the term "fowl" is particularly intended to encompass hens, cocks and drakes of chickens, turkeys and ducks.
The term "protozoa" is intended to include those members of the subphyla Sarcomastigophora and Sprozoa of the phylum Protozoa. More particularly, the term "protozoa" as used herein is intended to include those genera of parasitic protozoa which are important to man because they either cause disease in man or his domestic animals. These genera are for the most part found classified in the superclass of Mastigophora of the subphylum Sarcomastigophora and the class of Telosporea of the subphylum Sporozoa in the classification according to Baker (1969). Illustrative genera of these parasitic protozoa include Histomonas, Trypanosoma, Giardia, Trichomonas, Eimeria, Isopora, Toxoplasma and Plasmodium.
3~ Excluded from the superclass of Mastigophora is the genus Leishmania, certain species of which cause the tropical disease of Leishmaniasis in man. Also, specifi-cally excluded from the genus Trypanosoma, as used in this invention, are the species Trypanosoma cruzi, which can cause Chagas' disease in man, and the species M-1~76-Cl :11746~3 Trypanosoma lewisi. The compounds described herein have been found not to be particularly effective against these species.
On the other hand, the compounds of Formula I are particularly useful in inhibiting the growth of Trypanosoma brucei, the causative agent for nagana, or the tsetse-fly disease of horses and cattle in central Africa. The compounds described herein are also re-markably effective in inhibiting the growth of Eimeria tenella, a species of protozoa causing coccidiosis in fowl.
Indeed, a preferred embodiment of the present invention is the use of these compounds to inhibit the growth of intestinal coccidia in commercial poultry.
The economic importance of intestinal coccidia is highly significant. Thus in 1972, the estimated loss to the poultry industry in the United States due to coccidial infections was approximately 47 million dollars. Due to the rapid development of drug resistance by coccidia, and due to the relatively high toxicity of some of the drugs used in the treatment of coccidiosis, there is a need for effective coccidiostats that are non-toxic and to which intestinal coccidia do not develop rapid drug resistance.
It is not exactly understood how the compounds of this invention are able to inhibit the growth of protozoa.
Inter alia, the compounds described herein are irreversi-ble inhibitors of ornithine decarboxylase and S-adenoxylmethionine decarboxylase. As irreversible inhibitors of these enzymes, these compounds inhibit polyamine formation which may be required for protozoal cell division. In any event, the practice of this invention is not limited to any particular mode or theory of action whereby the compounds of this invention are able to effectively inhibit the growth of protozoa.
M-1076-Cl :a~746~3 The effect of the compounds of general for~ula (I) upon the growth of protozoa, and more particularly upon the growth of coccidia, can be demonstrated using Eimeria tenella and two week old male white leghorn chicks as the test animals. The birds are kept in batteries and both the infected and non-infected birds are housed in separate rooms to assure the maintenance of coccidia-free birds.
Each experimentally infected bird receives lO0,000 sporylated oocysts via gavage. The test compound is administered in the particular dosage desired through the drinking water and drug-free mash is provided ad libitum.
To evaluate the effect of the active ingredient on E
tenella infections, the chicks are sacrificed with carbon dioxide, necropsied, generally at day five of the study, and cecal lesions evaluated.
The inhibition of protozoal growth can also be determined using Trypanosoma brucei brucei, which is the causative agent of bovine trypanosomiasis (nagana) in Africa. The related species Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense are the causative agents for African sleeping sickness in humans.
In general, drug activity is tested against established infections of a pleomorphic EATRO 110 isolate of T. b.
brucei in mice. Test animals are infected with 5 x 105 parasites twenty four hours prior to testing. Control animals so infected generally die 5 days subsequent to innoculation. The compound to be tested is ad~inistered to the test animals via their drinking water in varying dosages. Animals cured of the infection remain parasite-free more than 30 days after the deaths of the controlanimals as indicated by an examina~ion of blood smears.
The compounds described herein are employed in M-1076-Cl amounts that are effective in inhibiting protozoal growth.
These amounts will depend, of course, upon various factors, such as the type and nature of the protozoal infection, the activity of the specific compound, the age, sex and species of animal treated and whether the treatment is prophylactic or therapeutic. In general, the compounds described herein can be orally or parenterally administered at a daily dose ranging from 5 mg/kg to 7 g/kg. Preferably, in the case of Trypanosoma infections the dosage range is from about 600 mg/kg to about 2 g/kg. In the case of Eimeria in-fections the dose can be lowered, ranging from about 15 mg/kg to about 1 g/kg.
Due to the low toxicity of the compounds described herein, the compounds can be safely administered ad libitum via the drinking water of the test animals in the treatment of coccidiosis in fowl. Generally speaking, concentrations of the active ingredient ranging from about 0.01% to about 2~ are suitable, depending primarily upon the nature of the protozoal infection to be treated whether prophylactic or therapeutic, the severity of the infection and the period of treatment.
Thus, for example the compound 2-difluoromethyl-2,5-diaminopentanoic acid can be effectively administered to chickens for the treatment of coccidiosis one day prior to infection as a 2% solution. Alternatively, a prophylactic course of treatment can be utilized 8 days prior to in-fection utilizing concentrations of 2-difluoromethyl-2,5-diaminopentanoic acid as low as 0.015~ in the drinking water of chickens. Preferably, a prophylactic concentra-tion of from 0.06% to about 1.0% is preferred.
This prophylactic treatment for the inhibition of protozoal growth provides one of the principle advantages to the use of the decarboxylase inhibitors described herein.
Thus, in the case of coccidia infections in chickens, for example, Eimeria tenella grows intracellularly in M-1076-Cl 4~;~3 the epithelial cells of the caecum as a trophozoite stage. Subsequently, these cells undergo a form of multiple mitosis to form a large number of merozoites.
These merozoites are released as the host cell lyses and serve to extensively infect fresh cells. The result is that the wall of the caecum is badly damaged, leading to severe blood and fluid loss and finally death. More-over, during the life cycle of E. tenella, resistant oocysts are produced which are voided in the faeces of chickens. Chickens being coprophagous in nature, the disease is rapidly spread by contamination of their food supply. Accordingly, coccidial infections in commercial flocks, when they occur, are epidemically treated with massive doses of currently available chemotherapeutic agents, that are primarily cidal in nature. Consequently, medicated feeds are now routinely employed in commercial flocks, so that all commercial fowl now receive almost constant medication to prevent outbreaks of coccidiosis from occurring.
The fact that the decarboxylase inhibitors herein described can be prophylactically administered, enables the host to overcome either a subsequent natural or artificial induced infection enzymatically via an inhi-bitory mechanism rather than via a cidal action. Thus, in the case of an E. tenella infection, the infection is curtailed in a manner that enables the host to avail itself of its own body defense mechanisms. The resulting antibodies which are produced via such a controlled infection, serve to further permanently immunize the host from future E. tenella infections.
The pharmaceutical compositions that are particularly suited for the prophylaxis or treatment of protozoal infec-tions in fowl comprise the heretofore described ~-substituted-amines or the ~-substituted-~-amino acids in combination M-1076-Cl ~1'74~ 3 with a pharmaceutically acceptable carrier. Advantageously, the antiprotozoal compositions are prepared by admixing the active compound with an inert carrier material. Typical carriers include talc, clay, pumice, silica, chalk, diatomaceous earth, walnut shell flour and equivalents thereof. Alternatively, the active ingredient can be admixed with a commercial feedstuff or vitamin and mineral pre-mix particularly adapted for fowl.
In most cases a concentrated aqueous solution of the active ingredient is employed in the management and treat-ment of coccidiosis in fowl. The compounds described, for the most part, are highly soluble, particularly in the form of their salts. Such solutions may advantageously contain preservatives, such as parabens, benzyl alcohol, phenol or thimerosal. In addition, isotonic agents, sugars, stabilizing or buffering agents can be usefully employed.
The compounds of formula (I) can be used in conjunction with other known drugs currently in use for the chemotherapy and chemoprophylaxis of disease caused by parasitic protozoa.
Generally, this has the effect of decreasing the amount of enzyme inhibitors administered. Such drugs include, among others: Antrycide, quinapyramine; Berenil, Diminazene aceturate; Pentamidine isethionate; Primaquine; Tryparsamide;
Amicarbalide; Amprolium; Amphotericin B; quinine; ~onensin;
Minocycline, 7-dimethylamino-6-demethyl-6-deoxytetracycline;
Clindamycin, 7-deoxy-7(S)-chlorolincomycin; Buquinolate;
Robenidine; and Nicarbazin. In some instances the compounds of formula (I) actually enhance or potentiate the effects of these drugs.
Of particular interest in this regard is the compound 2,5-diamino-2-difluoromethylpentanoic acid which has been shown to act synergistically with the antiprotozoal agents Antrycide, quinapyramine, Pentamidine isethionate and M-1076-Cl :~17~6~3 Amicarbalide. Thus, the 2,5-diamino-2-difluoromethyl-pentanoic acid concentration can be reduced by about four-fold when used in combination with subcurative doses (less than 1.0 mg/kg) of these drugs.
Additionally, the compounds of formula (I) can be used in combination with other known cytotoxic agents for the chemotherapy and chemoprophylaxis of parasitic diseases, particularly trypanosomiasis. Such cytotoxic agents include the antineoplastic antibiotic Bleomycin as well as other well-known cytotoxic agents, as for example, cyclophosphamide, methotrexate, prednisone, 6-mercaptopurine, procarbozine, daunorubicin, vincristine, vindesine, vinblastine, chlorambucil, cytosine arabinoside, 6-thioguanine, thio TEPA, 5-fluorouracil, 5-fluoro-2-deoxyuridine, 5-azacytidine, nitrogen mustard, 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU), busulfan or adriamycin.
Of particular interest in the treatment of trypanoso-miasis in general, and more particularly in the treatment of nagana in cattle, is the use of the enzyme inhibitor 2,5-diamino-2-difluoromethylpentanoic acid in combination with the antitumor antibiotic Bleomycin. This particular enzyme inhibitor appears to act synergistically with Bleomycin. Thus, mice infected with Trypanosoma brucei are cured after three days upon daily i.p. administration of Bleomycin at a dosage of 7 mg/kg. Similarly, trypanosome infections in mice are cured by the adminis-tration of a 1% solution of 2,5-diamino-2-difluoromethyl-pentanoic acid in the drinking water for 3 days.
The results of several combination experiments indicate that cures are consistently effected with 0.5 mg/kg of Bleomycin in combination with 0.5~ of 2,5-diamino-2-difluoromethylpentanoic acid administered via drinking water. Alternatively, cures are effected with concentrations M-1076-Cl ~7~6~3 of 0.25 mg/kg of Bleomycin in combination with only 0.25%
of 2,5-diamino-2-difluoromethylpentanoic acid in the drinking water. A combination of 0.1 mg/kg of Bleomycin and 0.1% of 2,5-diamino-2-difluoromethylpentanoic acid has no effect. Thus, the curative dosage combinations reflect a reduction in Bleomycin drug dosage of from 1/2 to 1/28 of the curative dose of the drug used singly, when used in combination with a subcurative dose of from 1/2 to 1/4 of the curative dose of 2,5-diamino-2-difluoromethylpentanoic acid.
The invention described and claimed herein is moreparticularly illustrated in conjunction with the following Examples specifically describing how the compounds of this invention can be prepared and utilized.
2-Difluoromethyl-2,5-diaminopentanoic acid Under nitrogen a solution (500 ml) of 2M butyl-lithium in hexane is added to a stirred solution of 143.1 ml of diisopropylamine in l.S liters of tetrahydrofuran at -78C after which 261 g (0.81 mole) of ornithine di-benzaldimine methyl ester in 1.5 liters of tetrahydrofuran is added. Upon completion of the addition the reaction temperature is raised to 40C and maintained between 40 and 50C for 3 hours during which time chlorodifluoro-methane gas is bubbled through the mixture with stirring.
The reaction mixture is then treated with a saturated solution of sodium chloride. The organic material is extracted with ether, and the ether extract washed several times with sodium chloride solution, dried over magnesium sulfate and evaporated to give a viscous oil.
The oil is stirred with lN HCl (1.5 1) for 3 hours, the mixture extracted several times with chloroform and the aqueous solution evapo.ated to dryness. The oily residue is refluxed with 12N hydrochloric acid (1.5 1) M-1076-Cl ~7a~6!r~3 for 16 hours, the cooled solution clarified by chloro-form extraction before concentration, decolorization (charcoal), and further concentration to about 750 ml.
The pH of the solution i5 adjusted to 3.5 by the 2ddition S of triethylamine, the ~olution treated again with char-coal before concentration to about 5û0 ml and dilution with 7-8 liters of acetone. The precipitated product is filtered off and washed with ethanol. The crude product is recrystallized by dissolving in about 150 ml hot 10 water and treatment of the solution with hot ethanol (450 ml). On cooling crystals of 2-difluoromethyl-2,5-diaminopentanoic acid hydrochloride monohydrate separaLe 71 g (37%), m.p. 183C.
lS ~-Ethynyl-~,~-diaminovaleric acid 11.~ g (0.048 M) of N-(3-trimethylsilylprop-2-ynyl)-. .
benzenecarboximidate in 20 ml of tetrahydrofuran is added to lithium diisopropylamide, prepared from 4.9 g (6.78 ml, 0.048 M) of diisopropylamide in 60 ml of tetrahydrofuran 20 and 23.6 ml of 2.05 M solution of n-butyllithium at -70C
after which 9.5 g (0.042 M) of N-(3-bromopropyl)benzylimine is added, and the mixture is stirred at -70C for 5-1/2 hours. To the reaction mixture is added 23.6 ml of a 2.05 M solution of n-butyllithium followed by the addition 25 of 4 5 g (3.67 ml, 0.048 M) of methyl chloroformate.
After 30 minutes at -78C the mixture is treated with brine, and the reaction product ls isolated by ether extraction. The ether extract is e~aporated and 300 ml of 3 N HCl is added to the resulting residue and the 30 mixture is refluxed for 7 hours. On cooling the mixture is washed well with methylene chloride, made alkaline and washed again. The aqueous solution is acidified and concentrated to dryne ,s. The residue is triturated with ethanol, filtered and the ethanol ~vaporated. The residue ` 11746~3 M-1076-Cl is dissolved in water, the pH adjusted to 6, and the solution is applied to a column of Amberlite 120 H+, eluting with 1 M NH40H which affords, upon recrystalliza-tion from ethanol-water, ~-ethynyl-~, ~-diaminovaleric acid, M.P. 168-169 (dec.).
In the above procedure N-(3-bromopropyl)benzylimine is prepared from 3-bromopropylamine and benzaldehyde by procedures generally known in the art.
1-Fluorometh 1-1 4-butanediamine dihvdrochloride Y
To a solution of 40 mmole of diazomethane in 110 ml of ether cooled to 0C and magnetically stirred is added under nitrogen dropwise over a period of 1 hour a solution of 20 ml of 4-phthalimidobutyryl chloride in 75 ml of ether. Stirring is continued for 1 hour at 25C after which the reaction mixture is added to a solution of 40 ml of HF/pyridine precooled to 0C. The resulting heterogeneous mixture is stirred at 25C for 1-1/2 hours and then poured on ice water. The ether phase is separated, washed with a solution of bicarbonate, then with brine and dried over magnesium sulfate. Concentra-tion of the solvent under reduced pressure affords a solid which is recrystallized from diethylether/pentane to give fluoromethyl 3-phthalimidopropyl ketone, m.p.
92C.
To a solution of 550 mg (2.2 mmole) of fluoromethyl 3-phthalimidopropyl ketone in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol cooled to -20C is added a solution of 0.8 mmole of sodium borohydride in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol precooled to -20C. The reaction mixture is stirred for 15 minutes at -20C and then neutralized with 2 M ~Cl to a pH of 1. The solvents are evaporated under reduced pressure and the residue is partitioned between water * Trade Mark ~ ~746~3 M-1076-Cl and chloroform. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give a residue which is recrystallized from tetrahydrofuran-diethylether to afford l-fluoro-5-phtllalimido-2-pentanol, m.p. 85C. A mixture of 264 mg (1.05 mmole) of l-fluoro-
5-phthalimido-2-pentanol, 170 mg (1.05 mmole) of the phthalimide, 302 mg (1.05 mmole) of triphenylphosphine and 201 mg (1.15 mmole) of diethylazodicarboxylate in 8 ml of tetrahydrofuran is stirred under nitrogen for 2 hours at 25C. The solvent is evaporated under reduced pressure and the residue taken up in benzene. The insoluble material is discarded and the residue obtained after con-centration of the filtrate is recrystallized from tetra-hydrofuran-diethylether to give l-fluoromethyl-1,4-butane-diyl-bis-phthalimide, m.p. 112C. A suspension of 3.1 g of l-fluoromethyl-1,4-butanediyl-bis-phthalimide in 140 ml of concentrated HC1 is heated at a reflux temperature for 3 days. The phthalic acid which precipitates on cooling to 4C is filtered off. The filtrate is concentrated to about 20 ml and cooled to 4C. The remaining phthalic acid which separates is filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with 40 ml of boiling isopropyl alcohol 3 times and then recrystallized from absolute ethanol to give 1-fluoromethyl-1,4-butanediamine dihydrochloride, m.p.
154C.
l-Fluoromethyl-4-methyl-1,4-butanediamine dihydrochloride To a solution of 40 mmole of diazomethane in 110 ml of ether cooled to 0C and magnetically stirred is added under nitrogen dropwise over a period of 1 hour a solution of 20 ml of 4-phthalimido-4-metnylbutyryl chloride in 7S
ml of ether. Stirring is continued for 1 hour at 25C
after which the reaction mixture is added to a solution M-1076-Cl 11746~3 of 40 ml of HF/pyridine precooled to oC. The resulting heterogeneous mixture is stirred at 25C for 1-1/2 hours and then poured on ice water. The ether phase is separated, washed with a solution of bicarbonate, then with brine and dried over magnesium sulfate. Concentration of the solvent under reduced pressure affords a solid which is recrystal-lized from diethylether/pentane to give fluoromethyl 3-phthalimido-3-methylpropyl ketone.
To a solution of 550 mg (2.2 mmole) of fluoromethyl 3-phthalimido-3-methylpropyl ketone in a mixture o 5 ml of tetrahydrofuran and 5 ml of methanol cooled to -20C is added a solution of 0.8 mmole of sodium borohydride in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol precooled to -20C. The reaction mixture is stirred for 15 minutes at -20C and then neutralized with 2 M HCl to a pH of 1. The solvents are evaporated under reduced pressure and the residue is partitioned between water and chloroform. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give a residue which is recrystallized from tetrahydrofuran-diethylether to afford l-fluoro-5-phthalimido-5-methyl-2-pentanol. A
mixture of 264 mg (1.05 mmole) of 1-fluoro-5-phthalimido-5-methylpentanol, 170 mg (1.05 mmole) of the phthalimide, 302 mg (1.05 mmole) of triphenylphosphine and 201 mg (1.15 mmole) of diethylazodicarboxylate in 8 ml of tetrahydro-furan is stirred under nitrogen for 2 hours at 25C. the solvent is evaporated under reduced pressure and the residue taken up in benzene. The insoluble material is discarded and the residue obtained after concentration of the filtrate is recrystallized from tetrahydrofuran-diethylether to give l-fluoromethyl-4-methyl-1,4-butane-diyl-bis-phthalimide. A suspension of 3.1 g of l-fluoro-methyl-4-methyl-1,4-butanediyl-bis-phthalimide in 140 ml of concentrated HCl is heated at reflux temperature for 3 days. The phthalic acid which precipitates on cooling M-1076-Cl :~174~3 to 4C is filtered off. The filtrate is concentrated to about 20 ml and cooled to 4C. The remaining phthalic acid which separates is filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with 40 ml of bolling isopropyl alcohol 3 times and then recrystallized from absolute ethanol to give l-fluoromethyl-4-methyl-1,4-butanediamine dihydrochloride.
l-Ethynyl-4-methyl-1,4-butanediamine To 10.8 g (0.05 M) of 3-trimethylsilylprop-2-ynyl-1-iminobenzyl in 500 ml of tetrahydrofuran under nitrogen atmosphere at -78C is added n-butyllithium (0.05 M).
After 10 minutes the dark red carbanion is treated with 11.3 g (0.05 M) of 4-bromo-2-iminobenzylbutane in 20 ml of tetrahydrofuran. After 3 hours at -78C, fifty ml of water is added and the tetrahydrofuran is evaporated leaving a residue which is heated at reflux under nitrogen atmosphere with 100 ml of 6 N hydrochloric acid for 48 hours. Upon cooling the aqueous solution is washed with methylene chloride, made alkaline with aqueous sodium hydroxide and reextracted with methylene chloride. The methylene chloride extract is dried over magnesium sul-fate, filtered, concentrated and distilled to afford 1-ethynyl-4-methyl-1,4-butanediamine.
Granules suitable for addition to the drinking water of poultry are prepared as follows:
Grams 2-Difluoromethyl-2,5-diaminopentanoic acid 33.0 Corn starch 18.5 Lactose 48.2 Zinc stearate 0.3 100 .0 - M-1076-Cl 117~ 3 The 2-difluoromethyl-2,5-diaminopentanoic acid is mixed with approximately 6 to 9 grams of lactose and passed through a fluid energy mill or micronizer to give a particle size of 1-25 microns~ Water, 35 ml, is added to approximately 2.0 grams of the corn starch and blended to prepare a 5% starch paste. The micronized 2-difluoro-methyl-2,5-diaminopentanoic acid - lactose powder, the remaining lactose and the remaining corn starch are well blended. The starch paste is added and blended, and the resulting mixture is passed through a No. 12 mesh screen.
The resulting granules are dried at 38C to a moisture content of approximately 3%, ground through a U.S.
Standard No. 12 screen and lubricated by mixing with 0.3 grams of zinc stearate.
A 10~ stock solution for use in the treatment of coccidiosis is prepared by dissolving 37.5 grams of 2-difluoromethyl-2,5-diaminopentanoic acid in one gallon of water at room temperature. One part of this stock solution diluted with nine parts of water results in the preparation of a 1~ medicated drinking water solution for poultry which is useful for the prevention of coccidiosis in poultry.
A medicated animal feed suitable for poultry is prepared utilizing the following ingredients. The birds are fed the medicated feed ad libitum.
'.
.
.:
M-1076-Cl ~1746~33 Percent by weight Ground yellow corn......................... 60.3 Soy bean oil meal.......................... 33.0 Alfalfa leaf meal.......................... 1.0 Dicalcium phosphate........................ 3.0 Calcium carbonate.......................... 1.0 Iodized salt............................... 0.2 2-difluoromethyl-2,5-diaminopentanoic acid. .33 Vitamin-mineral-amino acid antibiotic mix to furnish the following per 100 pounds of feed:
Oxytetracycline....................... 0.5 gm Penicillin ~as procaine salt)......... 0.25 gm Manganese sulfate..................... 8 gm DL-methionine......................... 22.7 gm Riboflavin............................ 130 mg DL-calcium pantothenate............... 930 mg Niacin................................ 1400 mg Pyridoxine............................ 130 mg Vitamin B12........................... 1 mg Choline chloride...................... 22.7 gm Vitamin A............................. 300,000 units Vitamin D3............................ 25,000 units The following illustrates the effect of 2-difluoro-methyl-2,5-diaminopentanoic acid on Trypanosoma brucei brucei infections in mice.
Groups of five mice weighing 20-25 g are innoculated with _ b. brucei (EATRO 110 isolate; 5 x 105 organisms/-mouse). The compound is administered via drinking water, _ libitum, 24 hours following infection. Results are expressed as average survival (in days) beyond the death of the control animals, based upon an average survival of control animals of five days. Berenil (diminazene aceturate) is included as a control trypanocide. The results are indicated in Table I below.
-- M-1076-Cl 1174t~3 TABLE I
TotalAverage DrugTreatment regimen DoseSurvival (mg)(Days) None 52-difluoromethyl-2,5-diaminopentanoic acid 2% in drinkina water, 6 days 600a ~30b 2% in drinking water, 3 days 300a >30 1% in drinking water, 6 days 300a ~30 1% in drinking water, 3 days I50a >30 100.5% in drinking water, 3 days 75a 28.6 0.1% in drinking water, 3 days l5a 2 300 mg/kg p.o., daily 3 days 22.5 26.3 150 mg/kg p.o., daily 3 days 11.3 22.8 75 mg/kg p.o., daily 3 days 5.6 19.2 1550 mg/kg p.o., daily 3 days 3.8 0 2-methyl-2,5-diaminopentanoic acid 2~ in drinking water 3 days 3ooa o diminazene aceturate 2.5 mg/kg i.p. daily, 3 days 0.2 >30 a Based upon a daily intake of 5 ml water/25 g mouse/day b Considered curative. Animals survived ~1 month beyond controls; blood smears were negative for parasites after 1 month. Attempts at subinoculation of brain suspensions into uninfected animals remained negative 25after >30 days.
.
M-1076-Cl 117~6~3 The following Example illustrates the effect of a 2~
solution of 2-difluoromethyl-2,5-diaminopentanoic acid in the drinking water of chickens infected with oocysts of Eimeria tenella.
Twenty chickens are infected F~_ S at day 1 with 100,000 oocysts of E. tenella. Ten of the animals are given drinking water containing a 2~ solution of 2-difluoro-methyl-2,5-diaminopentanoic acid. The remaining animals serve as controls. By day 3 all of the control animals demonstrate clinical signs of the disease. On day 7 all of the animals are sacrificed, cecal lesions are macro-scopically examined and quantified as follows.
0 = No detectable macroscopic lesions.
+1 = Few scattered petechiae in the cecal wall; no thinkening of the wall and normal cecal contents present.
+2 = Lesions are numerous with noticeable loss in the cecal contents; cecal wall slightly thickened.
+3 = Large amounts of blood and tissue debris present, i.e., cecal cores; cecal wall greatly thickened, little if any normal cecal contents present.
+4 = Cecal wall greatly distended with much blood or cecal cores present. Cecal debris lacking or included in cores. (Dead bird also scores as +4.) TABLE II
Average Lesion Score For Lesion Scores In Individual Animals Group Controls +4 +3 +4 +4 +4 +4 +2 +4 +4 +4 3.6 ~N = 10) 2-difluorometh 1-2 5-diamino entanoic acid treated Y , P
(~ = 10) +1 +1 +0 +1 +1 +3 +4 +4 +1 +1 1.7 M-1076-Cl ~17~
Following essentially the same procedure as in the preceding Example, six chickens are administered a 2~
solution of 2-difluoromethyl-2,5-diaminopentanoic acid ~DFMO) in their drinking water for a period of 3 days. At day 1 this group of six chickens, in addition to two groups of ten chickens each, are all infected ~er os with 100,000 oocysts of _ tenella per chicken. One group of ten chickens serves as the control group, the other group of ten chickens receives a standard dose of Amprolium in their drinking water for the next 5 days. At present Amprolium is the coccidiostat of choice. On day 5 all of the animals are sacrificed and examined for evidence of disease using the lesion scoring index described in the preceeding Example. The following results are obtained.
TABLE III
Mean Lesion ~reatment No. Chickens Days of Treatment Score Control 10 --- 3.70 20 2% solution of DFMO 6 3 0 0.120% solution of Amprolium 10 5 0.3 The following Example illustrates the effect of varying doses of 2-difluoromethyl-2,5-diaminopentanoic acid on Eimeria tenella infections in chickens.
Following essentially the same procedure as in Example 10, the dosage of 2-difluoromethyl-2,5-diamino-propionic acid (DFMO) is varied as shown in Table IV below.
Treatment with DFMO is started at day -1. The chickens are infected per os at day 0, and treatment is continued 1~4f~3 for an additional 5 days or a total of 6 days. The birds are sacrificed at day 5 and examined for evidence of disease using the lesion scoring index described in Example 10.
TABLE IV
Mean Eesion Treatment No. Chickens Days of Treatment Score Control 7 --- 3.29 2% DF~O 6 6 0 101.0% DFMO 6 6 0.5 0.5~ DFMO 6 6 1.00 The following Example illustrates the effectiveness of a low prophylactic dose upon E1meria tenella lesions in chickens.
Following essentially the same procedure set forth in Example 10, but varying the dose of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) administered and the period of administration, the following results are obtained.
TABLE V
Mean ~esion Treatment No. Chickens Days of Treatment Score Control 9 --- 3.33 2% DFMO 9 -1 thru +5 0 25 1% DFMO 9 -1 thru +S 0 0.5% DFMO 9 -1 thru +5 0 0.25% DFMO 9 -8 thru +5 0.44 0.125% DFMO 9 -8 thru +5 0 0.0625~ DFMO 9 -8 thru +5 0.66 - ~-1076-Cl ~174ti~3 . EXAMPLE 14 The following Example illustrates the acquisition of a permanent immunity towards Eimeria tenella infections in chickens.
Birds that have previously been treated wtih 2-difluoro-methyl-2,5-diaminopentanoic acid at concentrations as low as 0.5% on days -8 through +5 relative to infection are challenged one week following completion of therapy as indicated in Table VI below. These results indicate that prophylactic therapy at low doses permits an adequate development of parasites in the absence of a disease state, thereby enabling the development of an immunity to sub-sequent E. tenella infections.
TABLE VI
No. of Days of Mean Lesion Mean Lesion Treatment Chickens Treatment Score-Initial Score-Final Control 9 --- 0 2.50 1.0% DFMO 9 -8 thru +5 0.33 0 0.5% DFMO g -8 thru +5 0 0
154C.
l-Fluoromethyl-4-methyl-1,4-butanediamine dihydrochloride To a solution of 40 mmole of diazomethane in 110 ml of ether cooled to 0C and magnetically stirred is added under nitrogen dropwise over a period of 1 hour a solution of 20 ml of 4-phthalimido-4-metnylbutyryl chloride in 7S
ml of ether. Stirring is continued for 1 hour at 25C
after which the reaction mixture is added to a solution M-1076-Cl 11746~3 of 40 ml of HF/pyridine precooled to oC. The resulting heterogeneous mixture is stirred at 25C for 1-1/2 hours and then poured on ice water. The ether phase is separated, washed with a solution of bicarbonate, then with brine and dried over magnesium sulfate. Concentration of the solvent under reduced pressure affords a solid which is recrystal-lized from diethylether/pentane to give fluoromethyl 3-phthalimido-3-methylpropyl ketone.
To a solution of 550 mg (2.2 mmole) of fluoromethyl 3-phthalimido-3-methylpropyl ketone in a mixture o 5 ml of tetrahydrofuran and 5 ml of methanol cooled to -20C is added a solution of 0.8 mmole of sodium borohydride in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol precooled to -20C. The reaction mixture is stirred for 15 minutes at -20C and then neutralized with 2 M HCl to a pH of 1. The solvents are evaporated under reduced pressure and the residue is partitioned between water and chloroform. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give a residue which is recrystallized from tetrahydrofuran-diethylether to afford l-fluoro-5-phthalimido-5-methyl-2-pentanol. A
mixture of 264 mg (1.05 mmole) of 1-fluoro-5-phthalimido-5-methylpentanol, 170 mg (1.05 mmole) of the phthalimide, 302 mg (1.05 mmole) of triphenylphosphine and 201 mg (1.15 mmole) of diethylazodicarboxylate in 8 ml of tetrahydro-furan is stirred under nitrogen for 2 hours at 25C. the solvent is evaporated under reduced pressure and the residue taken up in benzene. The insoluble material is discarded and the residue obtained after concentration of the filtrate is recrystallized from tetrahydrofuran-diethylether to give l-fluoromethyl-4-methyl-1,4-butane-diyl-bis-phthalimide. A suspension of 3.1 g of l-fluoro-methyl-4-methyl-1,4-butanediyl-bis-phthalimide in 140 ml of concentrated HCl is heated at reflux temperature for 3 days. The phthalic acid which precipitates on cooling M-1076-Cl :~174~3 to 4C is filtered off. The filtrate is concentrated to about 20 ml and cooled to 4C. The remaining phthalic acid which separates is filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with 40 ml of bolling isopropyl alcohol 3 times and then recrystallized from absolute ethanol to give l-fluoromethyl-4-methyl-1,4-butanediamine dihydrochloride.
l-Ethynyl-4-methyl-1,4-butanediamine To 10.8 g (0.05 M) of 3-trimethylsilylprop-2-ynyl-1-iminobenzyl in 500 ml of tetrahydrofuran under nitrogen atmosphere at -78C is added n-butyllithium (0.05 M).
After 10 minutes the dark red carbanion is treated with 11.3 g (0.05 M) of 4-bromo-2-iminobenzylbutane in 20 ml of tetrahydrofuran. After 3 hours at -78C, fifty ml of water is added and the tetrahydrofuran is evaporated leaving a residue which is heated at reflux under nitrogen atmosphere with 100 ml of 6 N hydrochloric acid for 48 hours. Upon cooling the aqueous solution is washed with methylene chloride, made alkaline with aqueous sodium hydroxide and reextracted with methylene chloride. The methylene chloride extract is dried over magnesium sul-fate, filtered, concentrated and distilled to afford 1-ethynyl-4-methyl-1,4-butanediamine.
Granules suitable for addition to the drinking water of poultry are prepared as follows:
Grams 2-Difluoromethyl-2,5-diaminopentanoic acid 33.0 Corn starch 18.5 Lactose 48.2 Zinc stearate 0.3 100 .0 - M-1076-Cl 117~ 3 The 2-difluoromethyl-2,5-diaminopentanoic acid is mixed with approximately 6 to 9 grams of lactose and passed through a fluid energy mill or micronizer to give a particle size of 1-25 microns~ Water, 35 ml, is added to approximately 2.0 grams of the corn starch and blended to prepare a 5% starch paste. The micronized 2-difluoro-methyl-2,5-diaminopentanoic acid - lactose powder, the remaining lactose and the remaining corn starch are well blended. The starch paste is added and blended, and the resulting mixture is passed through a No. 12 mesh screen.
The resulting granules are dried at 38C to a moisture content of approximately 3%, ground through a U.S.
Standard No. 12 screen and lubricated by mixing with 0.3 grams of zinc stearate.
A 10~ stock solution for use in the treatment of coccidiosis is prepared by dissolving 37.5 grams of 2-difluoromethyl-2,5-diaminopentanoic acid in one gallon of water at room temperature. One part of this stock solution diluted with nine parts of water results in the preparation of a 1~ medicated drinking water solution for poultry which is useful for the prevention of coccidiosis in poultry.
A medicated animal feed suitable for poultry is prepared utilizing the following ingredients. The birds are fed the medicated feed ad libitum.
'.
.
.:
M-1076-Cl ~1746~33 Percent by weight Ground yellow corn......................... 60.3 Soy bean oil meal.......................... 33.0 Alfalfa leaf meal.......................... 1.0 Dicalcium phosphate........................ 3.0 Calcium carbonate.......................... 1.0 Iodized salt............................... 0.2 2-difluoromethyl-2,5-diaminopentanoic acid. .33 Vitamin-mineral-amino acid antibiotic mix to furnish the following per 100 pounds of feed:
Oxytetracycline....................... 0.5 gm Penicillin ~as procaine salt)......... 0.25 gm Manganese sulfate..................... 8 gm DL-methionine......................... 22.7 gm Riboflavin............................ 130 mg DL-calcium pantothenate............... 930 mg Niacin................................ 1400 mg Pyridoxine............................ 130 mg Vitamin B12........................... 1 mg Choline chloride...................... 22.7 gm Vitamin A............................. 300,000 units Vitamin D3............................ 25,000 units The following illustrates the effect of 2-difluoro-methyl-2,5-diaminopentanoic acid on Trypanosoma brucei brucei infections in mice.
Groups of five mice weighing 20-25 g are innoculated with _ b. brucei (EATRO 110 isolate; 5 x 105 organisms/-mouse). The compound is administered via drinking water, _ libitum, 24 hours following infection. Results are expressed as average survival (in days) beyond the death of the control animals, based upon an average survival of control animals of five days. Berenil (diminazene aceturate) is included as a control trypanocide. The results are indicated in Table I below.
-- M-1076-Cl 1174t~3 TABLE I
TotalAverage DrugTreatment regimen DoseSurvival (mg)(Days) None 52-difluoromethyl-2,5-diaminopentanoic acid 2% in drinkina water, 6 days 600a ~30b 2% in drinking water, 3 days 300a >30 1% in drinking water, 6 days 300a ~30 1% in drinking water, 3 days I50a >30 100.5% in drinking water, 3 days 75a 28.6 0.1% in drinking water, 3 days l5a 2 300 mg/kg p.o., daily 3 days 22.5 26.3 150 mg/kg p.o., daily 3 days 11.3 22.8 75 mg/kg p.o., daily 3 days 5.6 19.2 1550 mg/kg p.o., daily 3 days 3.8 0 2-methyl-2,5-diaminopentanoic acid 2~ in drinking water 3 days 3ooa o diminazene aceturate 2.5 mg/kg i.p. daily, 3 days 0.2 >30 a Based upon a daily intake of 5 ml water/25 g mouse/day b Considered curative. Animals survived ~1 month beyond controls; blood smears were negative for parasites after 1 month. Attempts at subinoculation of brain suspensions into uninfected animals remained negative 25after >30 days.
.
M-1076-Cl 117~6~3 The following Example illustrates the effect of a 2~
solution of 2-difluoromethyl-2,5-diaminopentanoic acid in the drinking water of chickens infected with oocysts of Eimeria tenella.
Twenty chickens are infected F~_ S at day 1 with 100,000 oocysts of E. tenella. Ten of the animals are given drinking water containing a 2~ solution of 2-difluoro-methyl-2,5-diaminopentanoic acid. The remaining animals serve as controls. By day 3 all of the control animals demonstrate clinical signs of the disease. On day 7 all of the animals are sacrificed, cecal lesions are macro-scopically examined and quantified as follows.
0 = No detectable macroscopic lesions.
+1 = Few scattered petechiae in the cecal wall; no thinkening of the wall and normal cecal contents present.
+2 = Lesions are numerous with noticeable loss in the cecal contents; cecal wall slightly thickened.
+3 = Large amounts of blood and tissue debris present, i.e., cecal cores; cecal wall greatly thickened, little if any normal cecal contents present.
+4 = Cecal wall greatly distended with much blood or cecal cores present. Cecal debris lacking or included in cores. (Dead bird also scores as +4.) TABLE II
Average Lesion Score For Lesion Scores In Individual Animals Group Controls +4 +3 +4 +4 +4 +4 +2 +4 +4 +4 3.6 ~N = 10) 2-difluorometh 1-2 5-diamino entanoic acid treated Y , P
(~ = 10) +1 +1 +0 +1 +1 +3 +4 +4 +1 +1 1.7 M-1076-Cl ~17~
Following essentially the same procedure as in the preceding Example, six chickens are administered a 2~
solution of 2-difluoromethyl-2,5-diaminopentanoic acid ~DFMO) in their drinking water for a period of 3 days. At day 1 this group of six chickens, in addition to two groups of ten chickens each, are all infected ~er os with 100,000 oocysts of _ tenella per chicken. One group of ten chickens serves as the control group, the other group of ten chickens receives a standard dose of Amprolium in their drinking water for the next 5 days. At present Amprolium is the coccidiostat of choice. On day 5 all of the animals are sacrificed and examined for evidence of disease using the lesion scoring index described in the preceeding Example. The following results are obtained.
TABLE III
Mean Lesion ~reatment No. Chickens Days of Treatment Score Control 10 --- 3.70 20 2% solution of DFMO 6 3 0 0.120% solution of Amprolium 10 5 0.3 The following Example illustrates the effect of varying doses of 2-difluoromethyl-2,5-diaminopentanoic acid on Eimeria tenella infections in chickens.
Following essentially the same procedure as in Example 10, the dosage of 2-difluoromethyl-2,5-diamino-propionic acid (DFMO) is varied as shown in Table IV below.
Treatment with DFMO is started at day -1. The chickens are infected per os at day 0, and treatment is continued 1~4f~3 for an additional 5 days or a total of 6 days. The birds are sacrificed at day 5 and examined for evidence of disease using the lesion scoring index described in Example 10.
TABLE IV
Mean Eesion Treatment No. Chickens Days of Treatment Score Control 7 --- 3.29 2% DF~O 6 6 0 101.0% DFMO 6 6 0.5 0.5~ DFMO 6 6 1.00 The following Example illustrates the effectiveness of a low prophylactic dose upon E1meria tenella lesions in chickens.
Following essentially the same procedure set forth in Example 10, but varying the dose of 2-difluoromethyl-2,5-diaminopentanoic acid (DFMO) administered and the period of administration, the following results are obtained.
TABLE V
Mean ~esion Treatment No. Chickens Days of Treatment Score Control 9 --- 3.33 2% DFMO 9 -1 thru +5 0 25 1% DFMO 9 -1 thru +S 0 0.5% DFMO 9 -1 thru +5 0 0.25% DFMO 9 -8 thru +5 0.44 0.125% DFMO 9 -8 thru +5 0 0.0625~ DFMO 9 -8 thru +5 0.66 - ~-1076-Cl ~174ti~3 . EXAMPLE 14 The following Example illustrates the acquisition of a permanent immunity towards Eimeria tenella infections in chickens.
Birds that have previously been treated wtih 2-difluoro-methyl-2,5-diaminopentanoic acid at concentrations as low as 0.5% on days -8 through +5 relative to infection are challenged one week following completion of therapy as indicated in Table VI below. These results indicate that prophylactic therapy at low doses permits an adequate development of parasites in the absence of a disease state, thereby enabling the development of an immunity to sub-sequent E. tenella infections.
TABLE VI
No. of Days of Mean Lesion Mean Lesion Treatment Chickens Treatment Score-Initial Score-Final Control 9 --- 0 2.50 1.0% DFMO 9 -8 thru +5 0.33 0 0.5% DFMO g -8 thru +5 0 0
Claims (11)
1. A veterinary composition for the prophylaxis or treatment of protozoal infections in animals comprising:
a) a protozoal inhibiting amount of an .alpha.-substituted amino acid or an .alpha.-substituted amine having the formula wherein R1 is hydrogen or carboxy;
Y is selected from the group consisting of CH2F, CHF2, CF3 and C?CH;
Z is selected from the group consisting of H2N-(CH2)3, and H2N-CH2CH=CH; with the proviso that when R1 is hydrogen, Y cannot be CF3 and Z must be ; and the salts and individual optical isomers thereof, in combi-nation with b) a suitable carrier.
a) a protozoal inhibiting amount of an .alpha.-substituted amino acid or an .alpha.-substituted amine having the formula wherein R1 is hydrogen or carboxy;
Y is selected from the group consisting of CH2F, CHF2, CF3 and C?CH;
Z is selected from the group consisting of H2N-(CH2)3, and H2N-CH2CH=CH; with the proviso that when R1 is hydrogen, Y cannot be CF3 and Z must be ; and the salts and individual optical isomers thereof, in combi-nation with b) a suitable carrier.
2. A composition according to claim 1 wherein the .alpha.-substituted amino acid is 2,5-diamino-2-difluoromethyl-pentanoic acid.
3. A composition according to claim 1 wherein the animals are fowl, the carrier is water and the .alpha.-substituted amino acid is 2,5-diamino-2-difluoromethylpentanoic acid present at a concentration of from 0.01% to 2%.
4. A veterinary composition for the prophylaxis or treatment of protozoal infections in animals comprising:
a) a protozoal inhibiting amount of an .alpha.-substituted amino acid or an .alpha.-substituted amine having the formula wherein Rl is hydrogen or carboxy;
Y is selected from the group consisting of CH2F, CHF2, CF3 and C?CH;
Z is selected from the group consisting of H2N-(CH2)3, H2N-?-(CH2)2 and H2N-CH2CH=CH; with the proviso that when Rl is hydrogen, Y cannot be CF3 and Z must be H2N-?-(CH2)2; and the salts and individual optical isomers thereof, in combi-nation with b) an antiprotozoal agent selected from the group consisting of Antrycide, quinapyramine, Berenil, Diminazene, Pentamidine, Primaquine, Tryparsamide, Amicarbalide, Ampro-lium, Amphotericin B, quinine, Monensin, Minocycline, 7-dimethylamino-6-demethyl-6-deoxytetracycline, Clindamycin, 7-deoxy-7(S)-chlorolincomycin, Buquinolate, Robenidine and Nicarbazin, and c) a suitable carrier.
a) a protozoal inhibiting amount of an .alpha.-substituted amino acid or an .alpha.-substituted amine having the formula wherein Rl is hydrogen or carboxy;
Y is selected from the group consisting of CH2F, CHF2, CF3 and C?CH;
Z is selected from the group consisting of H2N-(CH2)3, H2N-?-(CH2)2 and H2N-CH2CH=CH; with the proviso that when Rl is hydrogen, Y cannot be CF3 and Z must be H2N-?-(CH2)2; and the salts and individual optical isomers thereof, in combi-nation with b) an antiprotozoal agent selected from the group consisting of Antrycide, quinapyramine, Berenil, Diminazene, Pentamidine, Primaquine, Tryparsamide, Amicarbalide, Ampro-lium, Amphotericin B, quinine, Monensin, Minocycline, 7-dimethylamino-6-demethyl-6-deoxytetracycline, Clindamycin, 7-deoxy-7(S)-chlorolincomycin, Buquinolate, Robenidine and Nicarbazin, and c) a suitable carrier.
5. A composition according to claim 4 wherein the .alpha.-substituted amino acid is 2,5-diamino-2-difluoromethyl-pentanoic acid.
6. A composition according to claim 4 wherein the antiprotozoal agent of paragraph b) is Antrycide, Pentamidine or Amicarbalide.
7. A composition according to claim 4 wherein the .alpha.-substituted amino acid is 2,5-diamino-2-difluoromethyl-pentanoic acid in combination with a synergistically effective amount of an antiprotozoal agent selected from the group con-sisting of Antrycide, Pentamidine and Amicarbalide.
8. A veterinary composition for the prophylaxis or treatment of protozoal infections in animals comprising:
a) a protozoal inhibiting amount of an .alpha.-substituted amino acid or an .alpha.-substituted amine having the formula wherein R1 is hydrogen or carboxy;
Y is selected from the group consisting of CH2F, CHF2, CF3 and C?CH;
Z is selected from the group consisting of H2N-(CH2)3, and H2N-CH2CH=CH; with the proviso that when R1 is hydrogen, Y cannot be CF3 and Z must be ; and the salts and individual optical isomers thereof, in combi-nation with b) a cytotoxic agent selected from the group consisting of Bleomycin, cyclophosphamide, methotrexate, prednisone, 6-mercaptopurine, procarbozine, daunorubicin, vincristine, vindesine, vinblastine, chlorambucil, cytosine arabinoside, 6-thioguanine, thio TEPA, 5-fluorouracil, 5-fluoro-2-deoxyur-idine, 5-azacytidine, nitrogen mustard, 1,3-bis(2-chloroethyl) -l-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitro-sourea (CCNU), busulfan and adriamycin, and c) a suitable carrier.
a) a protozoal inhibiting amount of an .alpha.-substituted amino acid or an .alpha.-substituted amine having the formula wherein R1 is hydrogen or carboxy;
Y is selected from the group consisting of CH2F, CHF2, CF3 and C?CH;
Z is selected from the group consisting of H2N-(CH2)3, and H2N-CH2CH=CH; with the proviso that when R1 is hydrogen, Y cannot be CF3 and Z must be ; and the salts and individual optical isomers thereof, in combi-nation with b) a cytotoxic agent selected from the group consisting of Bleomycin, cyclophosphamide, methotrexate, prednisone, 6-mercaptopurine, procarbozine, daunorubicin, vincristine, vindesine, vinblastine, chlorambucil, cytosine arabinoside, 6-thioguanine, thio TEPA, 5-fluorouracil, 5-fluoro-2-deoxyur-idine, 5-azacytidine, nitrogen mustard, 1,3-bis(2-chloroethyl) -l-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitro-sourea (CCNU), busulfan and adriamycin, and c) a suitable carrier.
9. A composition according to claim 8 wherein the .alpha.-substituted amino acid is 2,5-diamino-2-difluoromethyl-pentanoic acid.
10. A composition according to claim 8 wherein the cytotoxic agent of paragraph b) is Bleomycin.
11. A composition according to claim 8 wherein the .alpha.-substituted amino acid is 2,5-diamino-2-difluoromethyl-pentanoic acid in combination with a synergistically effective amount of Bleomycin.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15997380A | 1980-06-16 | 1980-06-16 | |
US159,973 | 1980-06-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1174603A true CA1174603A (en) | 1984-09-18 |
Family
ID=22574910
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000379588A Expired CA1174603A (en) | 1980-06-16 | 1981-06-11 | Method of inhibiting the growth of protozoa |
Country Status (17)
Country | Link |
---|---|
JP (1) | JPS5731613A (en) |
AT (1) | AT377180B (en) |
AU (1) | AU544990B2 (en) |
BE (1) | BE889230A (en) |
CA (1) | CA1174603A (en) |
CH (1) | CH651206A5 (en) |
DE (2) | DE3153623C2 (en) |
FR (1) | FR2484255A1 (en) |
GB (1) | GB2078735B (en) |
IE (1) | IE51300B1 (en) |
IL (1) | IL63087A (en) |
IT (1) | IT1171380B (en) |
NL (1) | NL194153C (en) |
NZ (1) | NZ197394A (en) |
PH (1) | PH16634A (en) |
SE (1) | SE460517B (en) |
ZA (1) | ZA813953B (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS58123555U (en) * | 1982-02-17 | 1983-08-23 | 三菱電機株式会社 | In-line electron gun assembly equipment |
NL8400927A (en) * | 1984-03-23 | 1985-10-16 | Philips Nv | DEVICE AND METHOD FOR MOUNTING AN INTEGRATED ELECTRON CANNON SYSTEM. |
DE3421384A1 (en) * | 1984-06-08 | 1985-12-12 | Standard Elektrik Lorenz Ag, 7000 Stuttgart | DEVICE FOR ASSEMBLING ELECTRONIC RADIATOR GENERATORS |
JPS62148462A (en) * | 1985-12-19 | 1987-07-02 | メレルダウフア−マス−テイカルズ インコ−ポレ−テツド | Novel method of controlling growth of protozoa |
DE3872213T2 (en) * | 1988-02-05 | 1993-01-28 | Merrell Dow Pharma | 5-SUBSTITUTED ORNITHIN DERIVATIVES. |
US5455234A (en) * | 1994-03-16 | 1995-10-03 | Ahluwalia; Gurpreet S. | Inhibition of hair growth |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ187377A (en) * | 1977-06-01 | 1981-05-15 | Merck & Co Inc | A-amino-a-substituted alkyl-a-fluoromethylacetic acids |
CA1121375A (en) * | 1977-07-01 | 1982-04-06 | Brian W. Metcalf | Derivatives of amines and amino acids |
US4182891A (en) * | 1977-07-01 | 1980-01-08 | Merrell Toraude Et Compagnie | α-Acetylenic derivatives of α-amino acids |
US4139563A (en) * | 1977-07-01 | 1979-02-13 | Merrell Toraude Et Compagnie | α-ACETYLENIC DERIVATIVES OF AMINES |
US4088667A (en) * | 1977-07-01 | 1978-05-09 | Merrell Toraude Et Compagnie | Lower alkyl 2-tri-(lower)alkylsilylacetylene-N-carbethoxyglycinates and process for using same |
CA1091661A (en) | 1977-07-11 | 1980-12-16 | Philippe Bey | .alpha.-HALOMETHYL DERIVATIVES OF .alpha.-AMINO ACIDS |
US4134918A (en) * | 1977-09-06 | 1979-01-16 | Merrell Toraude Et Compagnie | Alpha-halomethyl derivatives of amines |
-
1981
- 1981-06-11 AU AU71654/81A patent/AU544990B2/en not_active Expired
- 1981-06-11 NZ NZ197394A patent/NZ197394A/en unknown
- 1981-06-11 PH PH25759A patent/PH16634A/en unknown
- 1981-06-11 ZA ZA813953A patent/ZA813953B/en unknown
- 1981-06-11 SE SE8103678A patent/SE460517B/en not_active IP Right Cessation
- 1981-06-11 CA CA000379588A patent/CA1174603A/en not_active Expired
- 1981-06-12 DE DE3153623A patent/DE3153623C2/de not_active Expired - Lifetime
- 1981-06-12 IE IE1308/81A patent/IE51300B1/en not_active IP Right Cessation
- 1981-06-12 IL IL63087A patent/IL63087A/en not_active IP Right Cessation
- 1981-06-12 DE DE19813123295 patent/DE3123295A1/en active Granted
- 1981-06-15 CH CH3939/81A patent/CH651206A5/en not_active IP Right Cessation
- 1981-06-15 AT AT0266581A patent/AT377180B/en not_active IP Right Cessation
- 1981-06-15 NL NL8102863A patent/NL194153C/en not_active IP Right Cessation
- 1981-06-15 JP JP9208181A patent/JPS5731613A/en active Granted
- 1981-06-15 FR FR8111733A patent/FR2484255A1/en active Granted
- 1981-06-15 IT IT48684/81A patent/IT1171380B/en active
- 1981-06-15 GB GB8118326A patent/GB2078735B/en not_active Expired
- 1981-06-15 BE BE0/205104A patent/BE889230A/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
GB2078735A (en) | 1982-01-13 |
AU7165481A (en) | 1981-12-24 |
FR2484255A1 (en) | 1981-12-18 |
NL194153C (en) | 2001-08-03 |
JPS5731613A (en) | 1982-02-20 |
JPH0432052B2 (en) | 1992-05-28 |
ATA266581A (en) | 1984-07-15 |
DE3123295C2 (en) | 1990-07-12 |
BE889230A (en) | 1981-12-15 |
PH16634A (en) | 1983-12-05 |
IT8148684A0 (en) | 1981-06-15 |
SE460517B (en) | 1989-10-23 |
SE8103678L (en) | 1981-12-17 |
DE3123295A1 (en) | 1982-04-29 |
IE811308L (en) | 1981-12-16 |
AU544990B2 (en) | 1985-06-27 |
ZA813953B (en) | 1982-06-30 |
NL194153B (en) | 2001-04-02 |
IL63087A (en) | 1984-10-31 |
NZ197394A (en) | 1984-09-28 |
CH651206A5 (en) | 1985-09-13 |
AT377180B (en) | 1985-02-25 |
DE3153623C2 (en) | 1991-06-27 |
NL8102863A (en) | 1982-01-18 |
IE51300B1 (en) | 1986-11-26 |
IT1171380B (en) | 1987-06-10 |
FR2484255B1 (en) | 1984-12-14 |
GB2078735B (en) | 1985-05-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4399151A (en) | Method of inhibiting the growth of protozoa | |
US5091430A (en) | O6 -substituted guanine compounds and methods for depleting O6 -alkylguanine-DNA alkyltransferase levels | |
AU2016200765A1 (en) | Methods for treating fibromyalgia syndrome | |
US4134918A (en) | Alpha-halomethyl derivatives of amines | |
CS227019B2 (en) | Method of preparing (-)-n-methyl-3-(2-methylphenyloxy)-3-phenylpropylamine | |
CA1090790A (en) | .alpha.-ACETYLENIC DERIVATIVES OF AMINES | |
CA1174603A (en) | Method of inhibiting the growth of protozoa | |
US3228833A (en) | Anticoccidial compositions and methods of using same | |
JPS60166663A (en) | Novel 3,4,5-trihydroxypiperidine compound | |
US20240270682A1 (en) | Application of glutamine derivative in preparation of animal feed additive | |
US4336260A (en) | Method and compositions using 1-aryl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid for treating depression | |
Horton-Smith et al. | Sulphonamides in the treatment of caecal coccidiosis of chickens | |
DK159654B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF | |
GB2120244A (en) | Aminoalkadiene derivative | |
EP0187009B1 (en) | Compounds and compositions having anti-inflammatory and analgesic activity | |
US4267374A (en) | Derivatives of amines and amino acids | |
RU2174833C1 (en) | Preparation for prophylaxis and treatment of poultry with coccidiosis | |
US4707498A (en) | Fluorinated diaminoalkyne derivatives | |
US5945455A (en) | Amine and amidine containing compounds as weight reducing agents | |
Schildknecht et al. | Antiparasitic activity of natural and semisynthetic monensin urethanes | |
US3555085A (en) | Nitro-trifluoromethylthiobenzamides | |
US3476768A (en) | Thienylalanine | |
US3231467A (en) | Method of treating coccidiosis | |
US3639478A (en) | N n-alkylenebis(2-lower alkoxy) - 2-sub-stituted-alkanamidines) and their preparation | |
TWI613201B (en) | Novel inhibitors of phosphodiesterase type 5 and their therapeutic uses |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKEX | Expiry | ||
MKEX | Expiry |
Effective date: 20010918 |