MXPA01007584A - Ketolide antibiotics - Google Patents
Ketolide antibioticsInfo
- Publication number
- MXPA01007584A MXPA01007584A MXPA/A/2001/007584A MXPA01007584A MXPA01007584A MX PA01007584 A MXPA01007584 A MX PA01007584A MX PA01007584 A MXPA01007584 A MX PA01007584A MX PA01007584 A MXPA01007584 A MX PA01007584A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- cr4r5
- groups
- formula
- compound
- Prior art date
Links
- 239000003242 anti bacterial agent Substances 0.000 title abstract description 6
- 229940064005 Antibiotic throat preparations Drugs 0.000 title description 4
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 title description 4
- 229940042052 Antibiotics for systemic use Drugs 0.000 title description 4
- 229940042786 Antitubercular Antibiotics Drugs 0.000 title description 4
- 229940093922 Gynecological Antibiotics Drugs 0.000 title description 4
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 title description 4
- 229940079866 intestinal antibiotics Drugs 0.000 title description 4
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 title description 4
- 230000003115 biocidal Effects 0.000 title description 3
- 239000003835 ketolide antibiotic agent Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 120
- 239000011780 sodium chloride Substances 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 206010060945 Bacterial infection Diseases 0.000 claims abstract description 20
- 206010037075 Protozoal infection Diseases 0.000 claims abstract description 16
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 239000012453 solvate Substances 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- -1 azido, hydroxy Chemical group 0.000 claims description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 241000251468 Actinopterygii Species 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 10
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 9
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000005842 heteroatoms Chemical group 0.000 claims description 3
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 230000002140 halogenating Effects 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910014585 C2-Ce Inorganic materials 0.000 claims 1
- 201000009910 diseases by infectious agent Diseases 0.000 abstract description 33
- 239000003904 antiprotozoal agent Substances 0.000 abstract description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000000034 method Methods 0.000 description 11
- 239000000651 prodrug Substances 0.000 description 11
- 229940002612 prodrugs Drugs 0.000 description 11
- 238000004166 bioassay Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 241000606856 Pasteurella multocida Species 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000011081 inoculation Methods 0.000 description 7
- TXRPHPUGYLSHCX-UHFFFAOYSA-N Selectfluor Chemical compound F[B-](F)(F)F.F[B-](F)(F)F.C1C[N+]2(CCl)CC[N+]1(F)CC2 TXRPHPUGYLSHCX-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 230000000875 corresponding Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229940041033 Macrolides Drugs 0.000 description 5
- 241001293418 Mannheimia haemolytica Species 0.000 description 5
- 241000193996 Streptococcus pyogenes Species 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 5
- 125000004429 atoms Chemical group 0.000 description 5
- 229940079593 drugs Drugs 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000006011 modification reaction Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 241000271566 Aves Species 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N Potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 230000003000 nontoxic Effects 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- HCUOEKSZWPGJIM-YBRHCDHNSA-N (E,2E)-2-hydroxyimino-6-methoxy-4-methyl-5-nitrohex-3-enamide Chemical group COCC([N+]([O-])=O)\C(C)=C\C(=N/O)\C(N)=O HCUOEKSZWPGJIM-YBRHCDHNSA-N 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- 241000606768 Haemophilus influenzae Species 0.000 description 3
- 101700000225 NR4A3 Proteins 0.000 description 3
- 102100001666 OSCP1 Human genes 0.000 description 3
- 101700064966 OSCP1 Proteins 0.000 description 3
- 101710013972 PLSCR1 Proteins 0.000 description 3
- 101700036345 SGE1 Proteins 0.000 description 3
- 229940076185 Staphylococcus aureus Drugs 0.000 description 3
- 230000002378 acidificating Effects 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000000845 anti-microbial Effects 0.000 description 3
- 150000007514 bases Chemical class 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000002829 reduced Effects 0.000 description 3
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000004665 trialkylsilyl group Chemical group 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- SEULWJSKCVACTH-UHFFFAOYSA-N 1-phenylimidazole Chemical compound C1=NC=CN1C1=CC=CC=C1 SEULWJSKCVACTH-UHFFFAOYSA-N 0.000 description 2
- MQTOSJVFKKJCRP-BICOPXKESA-N Azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 2
- 241001148536 Bacteroides sp. Species 0.000 description 2
- 229960005069 Calcium Drugs 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 229940038705 Chlamydia trachomatis Drugs 0.000 description 2
- 241000193403 Clostridium Species 0.000 description 2
- 241000186216 Corynebacterium Species 0.000 description 2
- 241000194033 Enterococcus Species 0.000 description 2
- 241000194032 Enterococcus faecalis Species 0.000 description 2
- 241000194031 Enterococcus faecium Species 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 229940047650 Haemophilus influenzae Drugs 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N Lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 206010025169 Lyme disease Diseases 0.000 description 2
- 108020002144 NR4 subfamily Proteins 0.000 description 2
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 2
- 241000191992 Peptostreptococcus Species 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 206010038683 Respiratory disease Diseases 0.000 description 2
- 210000003491 Skin Anatomy 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- 241000191963 Staphylococcus epidermidis Species 0.000 description 2
- 241000193985 Streptococcus agalactiae Species 0.000 description 2
- 229940030998 Streptococcus agalactiae Drugs 0.000 description 2
- 229940031000 Streptococcus pneumoniae Drugs 0.000 description 2
- 229940076156 Streptococcus pyogenes Drugs 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 206010046577 Urinary tract infection Diseases 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- HGINCPLSRVDWNT-UHFFFAOYSA-N acrylaldehyde Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 238000009632 agar plate Methods 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Chemical class 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 229960004099 azithromycin Drugs 0.000 description 2
- 230000001580 bacterial Effects 0.000 description 2
- 244000052616 bacterial pathogens Species 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940009662 edetate Drugs 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 2
- 235000015110 jellies Nutrition 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229920000747 poly(lactic acid) polymer Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 210000001519 tissues Anatomy 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N β-Alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- FFDGPVCHZBVARC-UHFFFAOYSA-M 2-(dimethylamino)acetate Chemical class CN(C)CC([O-])=O FFDGPVCHZBVARC-UHFFFAOYSA-M 0.000 description 1
- UCUNFLYVYCGDHP-UHFFFAOYSA-N 2-azaniumyl-4-methylsulfonylbutanoate Chemical compound CS(=O)(=O)CCC(N)C(O)=O UCUNFLYVYCGDHP-UHFFFAOYSA-N 0.000 description 1
- 108020005097 23S Ribosomal RNA Proteins 0.000 description 1
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-M 3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]propanoate Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O GHOKWGTUZJEAQD-ZETCQYMHSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001963 4 membered heterocyclic group Chemical group 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N 5-hydroxylysine Chemical compound NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 206010000210 Abortion Diseases 0.000 description 1
- 206010000269 Abscess Diseases 0.000 description 1
- 241000606750 Actinobacillus Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 1
- 229940088710 Antibiotic Drugs 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N Azetidine Chemical class C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 229940092524 Bartonella henselae Drugs 0.000 description 1
- 241001518086 Bartonella henselae Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 241000588807 Bordetella Species 0.000 description 1
- 229940052491 Bordetella pertussis Drugs 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- 241001148534 Brachyspira Species 0.000 description 1
- 206010006451 Bronchitis Diseases 0.000 description 1
- 229960003563 Calcium Carbonate Drugs 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 206010051226 Campylobacter infection Diseases 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000008787 Cardiovascular Disease Diseases 0.000 description 1
- 206010008323 Cervicitis Diseases 0.000 description 1
- 241001647372 Chlamydia pneumoniae Species 0.000 description 1
- 229960005091 Chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N Chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229940107161 Cholesterol Drugs 0.000 description 1
- 229940090805 Clavulanate Drugs 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N Clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 229940038704 Clostridium perfringens Drugs 0.000 description 1
- 108010065152 Coagulase Proteins 0.000 description 1
- 241000224483 Coccidia Species 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241001518260 Corynebacterium minutissimum Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000008953 Cryptosporidiosis Diseases 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N Cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-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
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 241000605721 Dichelobacter nodosus Species 0.000 description 1
- 229950008913 Edisilate Drugs 0.000 description 1
- 229950005627 Embonate Drugs 0.000 description 1
- 206010014665 Endocarditis Diseases 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000520130 Enterococcus durans Species 0.000 description 1
- 229940032049 Enterococcus faecalis Drugs 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- 229950000206 Estolate Drugs 0.000 description 1
- 241000186394 Eubacterium Species 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N GABA Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 229960001731 GLUCEPTATE Drugs 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 229940049906 Glutamate Drugs 0.000 description 1
- 229960002449 Glycine Drugs 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229940093912 Gynecological Sulfonamides Drugs 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 230000036499 Half live Effects 0.000 description 1
- 206010019375 Helicobacter infection Diseases 0.000 description 1
- 229940037467 Helicobacter pylori Drugs 0.000 description 1
- VHHHONWQHHHLTI-UHFFFAOYSA-N Hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 210000000003 Hoof Anatomy 0.000 description 1
- 229960002591 Hydroxyproline Drugs 0.000 description 1
- 206010023332 Keratitis Diseases 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid zwitterion Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine zwitterion Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- 229940001447 Lactate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N Lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 241001148567 Lawsonia intracellularis Species 0.000 description 1
- 229940115932 Legionella pneumophila Drugs 0.000 description 1
- 241000589242 Legionella pneumophila Species 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229940041028 Lincosamides Drugs 0.000 description 1
- 241000186781 Listeria Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 208000004396 Mastitis Diseases 0.000 description 1
- 208000010315 Mastoiditis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 230000036650 Metabolic stability Effects 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000588655 Moraxella catarrhalis Species 0.000 description 1
- 241000186367 Mycobacterium avium Species 0.000 description 1
- 241000187482 Mycobacterium avium subsp. paratuberculosis Species 0.000 description 1
- 241000187478 Mycobacterium chelonae Species 0.000 description 1
- 241000186364 Mycobacterium intracellulare Species 0.000 description 1
- 241000186363 Mycobacterium kansasii Species 0.000 description 1
- 241000186362 Mycobacterium leprae Species 0.000 description 1
- 229940010383 Mycobacterium tuberculosis Drugs 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 241001138504 Mycoplasma bovis Species 0.000 description 1
- JDHILDINMRGULE-LURJTMIESA-N N(pros)-methyl-L-histidine Chemical compound CN1C=NC=C1C[C@H](N)C(O)=O JDHILDINMRGULE-LURJTMIESA-N 0.000 description 1
- 229940049964 Oleate Drugs 0.000 description 1
- 206010048685 Oral infection Diseases 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N Pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940051027 Pasteurella multocida Drugs 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229940067631 Phospholipids Drugs 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 241000605894 Porphyromonas Species 0.000 description 1
- 241000605861 Prevotella Species 0.000 description 1
- YGXCETJZBDTKRY-DZCVGBHJSA-N Pristinamycin IA Chemical compound N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2CCC(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O YGXCETJZBDTKRY-DZCVGBHJSA-N 0.000 description 1
- 208000010362 Protozoan Infections Diseases 0.000 description 1
- 206010037294 Puerperal pyrexia Diseases 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J Pyrophosphate Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 208000007865 Relapsing Fever Diseases 0.000 description 1
- 206010057190 Respiratory tract infection Diseases 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010039447 Salmonellosis Diseases 0.000 description 1
- 241000593989 Scardinius erythrophthalmus Species 0.000 description 1
- 206010040490 Sexually transmitted disease Diseases 0.000 description 1
- 206010040872 Skin infection Diseases 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N Sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 240000001016 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010061372 Streptococcal infection Diseases 0.000 description 1
- 229940115920 Streptococcus dysgalactiae Drugs 0.000 description 1
- 241000194042 Streptococcus dysgalactiae Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241001312524 Streptococcus viridans Species 0.000 description 1
- 108010015795 Streptogramin B Proteins 0.000 description 1
- 229940041030 Streptogramins Drugs 0.000 description 1
- 108010034396 Streptogramins Proteins 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 229940040944 Tetracyclines Drugs 0.000 description 1
- 206010044008 Tonsillitis Diseases 0.000 description 1
- 206010044248 Toxic shock syndrome Diseases 0.000 description 1
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 1
- 231100000765 Toxin Toxicity 0.000 description 1
- 241000589884 Treponema pallidum Species 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 206010068760 Ulcers Diseases 0.000 description 1
- 241000202921 Ureaplasma urealyticum Species 0.000 description 1
- 208000000143 Urethritis Diseases 0.000 description 1
- 208000006374 Uterine Cervicitis Diseases 0.000 description 1
- 206010046793 Uterine inflammation Diseases 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N VANCOMYCIN Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 Vancomycin Drugs 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- 241000606834 [Haemophilus] ducreyi Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 201000005661 acute cystitis Diseases 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960003692 aminobutyric acid Drugs 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000844 anti-bacterial Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 201000001320 atherosclerosis Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 1
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 229940000635 beta-Alanine Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OWIUPIRUAQMTTK-UHFFFAOYSA-N carbazic acid Chemical compound NNC(O)=O OWIUPIRUAQMTTK-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 230000001332 colony forming Effects 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- DKMROQRQHGEIOW-UHFFFAOYSA-N diethyl butanedioate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 101710037552 ermC Proteins 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-L galactarate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C([O-])=O DSLZVSRJTYRBFB-DUHBMQHGSA-L 0.000 description 1
- 229940013945 gamma-Aminobutyric Acid Drugs 0.000 description 1
- 201000000628 gas gangrene Diseases 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 244000052637 human pathogens Species 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 229940079867 intestinal antiinfectives Sulfonamides Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M laurate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 101700043910 mefA Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 201000005111 ocular hyperemia Diseases 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 229940005938 ophthalmologic antiinfectives Sulfonamides Drugs 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001717 pathogenic Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 201000007100 pharyngitis Diseases 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 125000005541 phosphonamide group Chemical group 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000865 phosphorylative Effects 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002633 protecting Effects 0.000 description 1
- 244000079416 protozoan pathogens Species 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229910052904 quartz Inorganic materials 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000003381 solubilizing Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N stearylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 201000010874 syndrome Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229940026752 topical Sulfonamides Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 108020003112 toxins Proteins 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N trans-L-hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 102000035402 transmembrane proteins Human genes 0.000 description 1
- 108091005683 transmembrane proteins Proteins 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 229960005486 vaccines Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical compound CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Abstract
This invention relates to compounds of formula (1) and to pharmaceutically acceptable salts and solvates thereof wherein X1, X2, R2, R8, R9, R10 and R11 are as defined herein. The compounds of formula (1) are antibacterial and antiprotozoal agents that may be used to treat various bacterial and protozoal infections and disorders related to such infections. The invention also relates to pharmaceutical compositions containing the compounds of formula (1) and to methods of treating bacterial and protozoal infections by administering the compounds of formula (1).
Description
ANTIBIOTICS CETO IDOS
BACKGROUND OF THE INVENTION
This invention relates to new macrolide derivatives which are useful as antibacterial and antiprotozoal agents in mammals, including humans, as well as in fish and birds. This invention further relates to pharmaceutical compositions containing the novel compounds and to methods of treating bacterial and protozoal infections in mammals, fish and birds, by administering the new compounds to mammals, fish and birds in need of such treatment. Macrolide antibiotics are known to be useful in the treatment of a broad spectrum of bacterial and protozoal infections in mammals, fish and birds. Such antibiotics include various derivatives of erythromycin A such as azithromycin, which is commercially available and is cited in U.S. Patents 4,474,768 and 4,517,359, which are incorporated herein by reference in their entirety. Other macrolide antibiotics are described and claimed in the published PCT International Application WO 98/56800 (published December 17, 1998), which designates the United States; U.S. Patent 5,527,780, issued June 18, 1996; United States provisional application number 60/101263 (filed September 22, 1998) (file number of agent PC 10406); U.S. Provisional Patent Application No. 60/111728 (filed December 10, 1998) (file number of Agent PC 10494); published PCT application WO 98/01546 (published January 15, 1998); published PCY application WO 98/01571 (published January 15, 1998); published European patent application number 949268 (published October 13, 1999); and U.S. Patent 5,747,467 (issued May 5, 1998). Each of the patents and patent applications of the United States, and previous European and PCT international patent applications are hereby incorporated by reference in their entirety. Like azithromycin and other macrolide antibiotics, the new macrolide compounds of the present invention possess activities against various bacterial and protozoal infections as described below.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula
and pharmaceutically acceptable salts and solvates thereof, wherein: X1 is O, -CR-R5- or -NR4-; X2 is = O or = NOR1; R1 is H or C1-C10 alkyl, with from 1 to 3 carbon atoms of said alkyl optionally replaced by a heteroatom selected from O, S and -N (R4) -, and said alkyl being optionally substituted with 1 to 3 selected substituents independently of the group consisting of -C- (O) O (C-rdo alkyl), C-1-C10 alkoxy, C1-C10 alkanoyl, halogen, nitro, cyano, 4- to 10-membered heterocyclyl, C1-C10 alkyl, - NR4R5, C6-C10 aryl, -S (O) n (C1-C10 alkyl), where n is an integer ranging from 0 to 2 and -SO2NR4R5; R2 is - (CR4R5) n (4 to 10 membered heterocycle) or - (CRR5) n (C6-C10 aryl), where n is an integer from 0 to 6, with 1 to 3 R or R groups of the portion - (CR 4 RGD5) Xn- of the above R groups optionally substituted with a halogen substituent, and the heterocyclic and aryl portions of the above R2 groups being optionally substituted with 1 to 4 R3 groups; each R 3 is independently selected from halogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C 1 -C 1 alkoxy, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl. -C (O) R6, -C (O) OR6, OC (O) R6, -NR6C (0) R7, -NR6C (0) NR1R7, -NR6C (0) OR7, -C (0) NR6R7, -NR6R7 , NR6OR7, -SO2-NR6R7, -S- (O) j (CrC6 alkyl), where j is an integer from 0 to 2, - (CR1R2) t (C6-C10 aryl), - (CR4R5) t (heterocycle of 4 to 10 members), - (CR4R5) qC (O) (CR4R5) t (ary C6 ~ C10), - (CR4-R5) qC (O) (CR4R5) t (heterocycle of 4 to 10 members), - ( CR4-R5) tO (CR4R5) q (aryl C6-C? 0), - (CR4R5) tO (CR4R5) q (heterocycle of 4 to 10 members), - (CR4R5) qS02 (CR4R5) t (ary C6-C10) and - (CR4R5) q-S02 (CR4R5) t (heterocycle of 4 to 10 members), each of q and t being, independently, an integer of 0 to 5, with 1 or 2 ring carbon atoms of the heterocyclic portions of the above R10 groups optionally substituted with an oxo portion (= 0 =) and, the alkyl, alkenyl, alkynyl, aryl and heterocyclic portions of the R10 groups being previous optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR6, -C (0) R6, -C (0) OR6, -OC (0) R6, -NR6C ( 0) R7, -C (0) NRdR7, -N-R6R7, -NR6OR7, C? -C? Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CR R5) t (C-C-io aryl) and - (CR4R5) t (heterocycle of 4 to 10 members), where t is an integer from 0 to 5; each of R 4 and R 5 is independently selected from H and C 1 -C 2 alkyl; each of R6 and R7 is independently selected from H, C6 alkyl, (CR4R5) t (C6-C10 aryl), and - (CR4R5) t- (4- to 10-membered heterocycle), where t is an integer from 0 to 5, with 1 or 2 ring carbon atoms of the heterocyclic group being optionally substituted with an oxo (= O) portion, and the alkyl, aryl and heterocyclic portions of the above groups R6 and R7 being optionally substituted with 1 to 3 substituents, selected independently of halogen, cyano, nitro, -NR R5, trifluoromethyl, trifluoromethoxy, C2-C6 alkyl, C2-C6 alkenyl, C3-C6 alkynyl, hydroxy and C6-C6 alkoxy; R 8 is H, -C (O) (C-t-Cß alkyl), benzyl, benzyloxycarbonyl or (C 1 -C 6 alkyl) 3 S ylyl; R9 is C? -C6 alkyl; R10 is H or C1-C10 alkyl; and R11 is selected from chlorine, bromine, iodine, fluoro and cyano; with the proviso that when X2 is = O, then R11 is cyano, or from 1 to 3 of the groups R4 or R5 of the portion -CR4-R5) n of the R2 groups mentioned above are Ct-Cß alkyl or are replaced by a halogen substituent. Specific embodiments of the present invention include compounds of formula 2 (which is a specific embodiment within the genus of formula 1)
wherein R12, R13, R14 and R15 are each independently selected from H, halogen, methyl and ethyl. More specific embodiments include the compounds of formula 2, wherein R14 and R15 are H and each of R12 and R13 is independently selected from H and methyl. In a preferred embodiment of the compounds of formula 2, each of R12, R13, R14 and R15 are H. Other specific embodiments of the present invention include compounds of formula 3 (which is a specific embodiment within the genus of formula 1 )
wherein R12, R13, R14 and R15 are each independently selected from H, halogen, methyl and ethyl, with the proviso that at least one of R12, R13, R14 and R15 is not H. More specific modalities include the compounds of formula 3, wherein R14 and R15 are both H, R12 is methyl and R13 is selected from H and methyl.
The invention further relates to a pharmaceutical composition for the treatment of a bacterial infection or a protozoal infection, or a disorder related to a bacterial or protozoal infection in a mammal, fish or bird, comprising a therapeutically effective amount of a compound of formula 1, or one of the pharmaceutically acceptable salts or solvates. The invention further relates to a method for treating a bacterial infection or a protozoal infection, or a disorder related to a bacterial or protozoal infection in a mammal, fish or bird, which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula 1, or one of the pharmaceutically acceptable salts or solvates thereof. The term "treat", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting progress or preventing the disorder or condition to which that term applies or one or more symptoms. of said disorder or condition. The term "treatment", as used herein, refers to the action of treating, being treated as it has just been defined. Tai and as used herein, unless otherwise indicated, the term "bacterial infection (s)", "protozoan infection (s)" and "disorders related to bacterial infections or infections. protozoa "include the following: pneumonia, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis, related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enterococcus faecalis, E. faecium, E. cassielavus, S. epidermidis , S. haemolyticus or Peptostreptococcus spp .; pharyngitis, rheumatic fever and glomerulonephritis associated with infection by Streptococcus pyogenes, groups of streptococci C and G, Corynebacterium diptheriae or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycopiasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae or Chamydia pneumoniae; infections in the blood and tissues, including endocarditis and osteomyelitis, caused by S. aureus, S. haemolyticus, E. faecalis, E. faecium, E. durans, including strains resistant to antibacterials known as, although not limited to them , beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides; infections and abscesses of the skin and soft tissue without complications and puerperal fever related to infection by Staphylococcus aureus, staphylococcoscoagulase negative (ie, S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, streptococcal groups CF (streptococci from small colonies), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., Or Bartonella henselae; acute urinary tract infections without complications related to infection by Staphylococcus aureus, coagulase-negative Staphylococcus species or Enterococcus spp .; urethritis and cervicitis; sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum or Neisseria gonorrheae; diseases caused by toxins related to infection by S. aureaus (intoxicated food and toxic shock syndrome) or streptococci of groups A, B and C; ulcers related to Helicobacter pylori infection; systemic febrile syndromes related to Borrelia recurrentis infection; Lyme disease related to Borrelia burgdorferi infection; conjunctivitis, keratitis and dacryocyst related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae or Listeria spp .; Mycobacterium avium disseminated complex (MAC) related to infection by Mycobacterium avium or Mycobacterium intracellulare; infections caused by Mycobacterium tuberculosis, M. leprae, M. paratuberculosis, M. Kansasii or M. Chelonei; gastroenteritis related to Campylobacter jejuni infection; intestinal protozoa related to infection by Cryptosporidium spp., odontogenic infection related to viridans streptococcal infection; persistent cough related to Bordetella pertussis infection; Gas gangrene related to infection by Clostridium perfringens or Bacteroides spp .; and atherosclerosis or cardiovascular disease related to infection by Helicobacter pylori or Chlamydia pneumoniae. Bacterial infections and protozoal infections and disorders related to such infections that can be treated or prevented in animals include the following: bovine respiratory disease related to infection by P. haemolytica, P. multocida, Mycoplasma bovis or Bordetella spp .; enteric disease of cattle related to infection by E. coli or protozoa (ie, coccidia, cryptosporidia, etc.); mastitis of dairy cows related to S. aureus infection, Strep. uberis, Streptococcus agalactiae, Streptococcus dysgalactiae, klebsiella spp., Corynebacterium or Enterococcus spp .; porcine respiratory disease related to infection by A. pleuro, P. multocida or Mycoplasma spp .; enteric swine disease related to infection by E. coli, Lawsonia intracellularis, Salmonella or Serpulina hyodysinteriae; the necrosis of the hoof in cows related to the infection by Fusobacterium spp .; Metritis vaccine related to E. coli infection; hairy warts in cows related to infection by Fusobacterium necrophorum or Bacteroides nodosus; the red eye of the cows related to the infection by Moraxella bovis; premature bovine abortion related to infection caused by protozoa (ie, neosporium); urinary tract infection in dogs and cats related to E. coli infection; skin and soft tissue infections in dogs and cats related to infection by S. epidermidis, S. inteimedios, Coagulase negative Staphylococcus or P. multocida; and dental or oral infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp .; Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other bacterial infections and protozoal infections and disorders related to such infections that can be treated or prevented according to the method of the present invention are cited in JP Sandord et al., "The Sanford Guide To Antimicrobial Therapy", 26th Edition (Antimicrobial Therapy, Inc., 1996). The term "halogen", as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred halogen groups are fluoro, chloro and bromo. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals with linear portions, cyclical and / or branched. It will be appreciated that to include cyclic portions, the alkyl group should include at least 3 carbon atoms. The term "alkenyl", as used herein, unless otherwise indicated, includes alkyl groups as defined above that have at least one carbon-carbon double bond at some point in the alkyl chain . The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl groups as defined above having at least one carbon-carbon triple bond at some point in the alkyl chain . The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as phenyl or naphthyl.
The term "4- to 10-membered heterocycle", as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms, each selected from 0, S and N, each of the heterocyclic groups having 4 to 10 carbon atoms in its ring system. The non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but the aromatic heterocyclic groups should have at least 5 atoms in their ring system. Heterocyclic groups include ring systems fused with benzene and ring systems substituted with one or more oxo moieties. An example of a 4-membered heterocyclic group is azetidinyl (azetidine derivative). An example of a 5-membered heterocyclic group is thiazolyl and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, tiepanyl, oxazepinyl, diazeoinyl, thiazepinyl, 1,3. , 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxoianilo, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3 -azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzoimidazolyl, bezofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, bezoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. When possible, the above groups, when they come from the compounds listed above, can be linked by C or linked by N. For example, a group derived from pyrrole can be pyrrol-1-yl (linked by N) or pyrrol-3-yl (joined by C). The term "pharmaceutically acceptable salt (s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of formula 1 The compounds of formula 1 which are basic in nature can form a wide variety of salts with various inorganic and organic acids. Acids which can be used to prepare the pharmaceutically acceptable acid addition salts of said basic compounds of formula 1 are those which form non-toxic acid addition salts, ie salts containing pharmacologically acceptable anions, such as acetate salts, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dichlorohydrate, edetate, edisilate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycolylaryl, hexylresorcinate , hydrabamine, hydrobromide, hydrochloride, iodide, ostothionate, lactate, lactobionate, laurate, malate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, theoclate, tosiiate, triethioiodide and valerate. The compounds of formula 1 which are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal and alkali earth metal salts and, in particular, the sodium and potassium salts. The present invention further includes all radioisotope-labeled forms of the compounds of formula 1 and pharmaceutically acceptable salts thereof, wherein the radioisotope is selected from 3H, 1C and 14C. Such compounds labeled with radioisotopes are useful as research or diagnostic tools. Certain compounds of formula 1 can have asymmetric centers and, therefore, exist in different enantiomeric forms. This invention relates to the use of all isomers and stereoisomers of the compounds of formula 1 and mixtures thereof. In particular, the invention includes the E and Z isomers of the group -OR1 (when X2 is = NOR1) attached to the nitrogen of the oxime portion at the C-9 position of the macrolide ring of formula 1. The present invention also includes compounds labeled with isotopes and pharmaceutically acceptable salts thereof, which are identical to those shown in formula 1, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, and 36CI , respectively. The compounds of the invention, their prodrugs and the pharmaceutically acceptable salts of said compounds and of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example, those incorporating radioactive isotopes such as 3 H and 1 C, are useful in drug assays and / or distribution in substrate tissues. The isotopes with tritium, that is, 3H and with carbon 14, that is, 14C, are particularly preferred for their ease of preparation and detection. In addition, replacement with heavier isotopes such as deuterium, ie, 2H, can provide certain therapeutic advantages derived from increased metabolic stability, for example, a longer half-life in vivo or from the need for lower doses and, therefore, can be preferred in certain circumstances. The isotope-labeled compounds of formula 1 of this invention and their prodrugs can be prepared in a general manner by carrying out the procedures described in the schemes and / or in the following examples and preparations, substituting an unlabelled reagent with isotopes for a reagent labeled with Isotope readily available. This invention further includes pharmaceutical compositions and methods for treating bacterial infections by administering prodrugs of the compounds of formula 1. Compounds of formula 1 having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds in which an amino acid portion, or a polypeptide chain of two or more (eg, two, three or four) amino acid portions is covalently linked via an amide or ester linkage to an amino, hydroxy or carboxylic group free of the compounds of formula 1. The amino acid portions include, but are not limited to, the 20 natural amino acids, commonly designated by three-letter symbols and also include 4-hydroxyproline, hydroxylysine, demosin, sodemosin, 3-methylhistidine. , norvaline, beta-alanine, gamma-aminobutyric acid, citrullinehomocysteine, homoserine, omitin and methionine sulfone. Other types of prodrugs are also contemplated. For example, free carboxyl groups can be derivatized in the form of amides or alkyl esters. Free hydroxy groups can be derivatized using groups including, hemisuccinates, phosphate esters, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, but without being limited thereto, as described in Advanced Drug Delivery Reviews, 1996, 19, 115. The carbamate prodrugs of hydroxy and amino groups are also included, as are the carbonate prodrugs, suifonate esters and sulfate esters of the hydroxy groups such as esters of (acyloxy) methyl and of (acyloxy) ethyl in which the acyl group can be an alkyl ester, optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functional groups , or in which the acyl group is an amino acid ester as described above. Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All these prodrug moieties may incorporate groups that include, but are not limited to, ether, amine and carboxylic acid functional groups.
DETAILED DESCRIPTION OF THE INVENTION
The preparation of the compounds of the present invention is illustrated in the following schemes:
SCHEME 1
fifteen
SCHEME 2
a SCHEME 2 (CONTINUED) SCHEME 2 (CONTINUED) 4 '
SCHEME 3
The preparation of the compounds of the present invention is illustrated in the above schemes. The starting materials and / or the final compounds of formula 1 in which R10 is a non-ethyl portion, within the definition of R10 illustrated above, can be prepared as described in published PCT applications WO 98/01571 (Biotica Tech. Ltd. and Pfizer Inc.) and WO 98/01546 (assigned to Biotica Tech. Ltd.). Other specific procedures that relate to the synthesis of the compounds of the present invention are cited in the PCT international patent application with publication number WO 98/38199 (published September 3, 1998), PCT international patent application with number WO 98/56800 (published December 17, 1998), United States Provisional Patent Application No. 60/101, 263 (filed September 22, 1998), United States Provisional Patent Application Number 60 / 111, 728 (filed December 10, 1998), European patent application number EP 487,411 and European patent application number EP 799,833. In the above schemes, all substituents are as defined for formula 1 above, unless otherwise indicated. The starting materials may or may not require appropriate protection of the functional group before various modifications take place and deprotection after the desired modifications are completed. The protecting groups most commonly used for amino portions in the macrolide compounds of this invention are the benzyloxycarbonyl (Cbz) and t-butyloxycarbonyl (Boc) groups. The hydroxyl groups are generally protected in the form of acetates, Cbz carbonates or a trialkylsilyl group. The hydroxyl group at the C-2 'position is a potentially reactive hydroxyl group among the numerous hydroxyl groups present in the macrolide compounds of the type claimed herein. The C-2 'hydroxyl group is selectively protected by treating the compound with one equivalent of acetic anhydride in dichloromethane in the absence of an external base. This process selectively converts the hydroxyl group to C-2 'in the corresponding acetate. The hydroxyl protecting group can be removed by treating the compound with methanol at a temperature ranging from about 0 ° C to 40 ° C to about 65 ° C for 10 to 48 hours. Other methods of protection and selective deprotection will be known to those skilled in the art. Referring to Scheme 1, the compound of formula 5, in which Ri1 is a halogen group and the portion substituents are as defined above, can be prepared by treating the compound of formula 4 with a base such as sodium hydride, potassium, potassium hexamethyldisilazide (KHMDS), pyridine, sodium carbonate or lithium diisopropylamide, preferably KHMDS with, and a halogenating agent such as N-fluorobencensulfonamida, SELECTFLUOR ™ (marketed by Air Products and Chemicals, Inc., Allentown, Pennsylvania, United States of America) for fluorac.ón, pyridinium tribromide or cyanogen bromide for the bromination, or hexachloroethane for chlorination, in a solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), N-methylpyrrolidone or CH2Cl2 , or a mixture of the above solvents, preferably DMF. The reaction temperature, which depends greatly on the reagent used, can vary from -78 ° C to 60 ° C. In this step, R8 is preferably a hydroxy protecting group such as an acetyl group, a benzyl group or a trialkylsilyl group. In order to provide the compound of formula 6, the deprotection of the hydroxy at position C-2 'can proceed using methanol, if R8 is an acetyl group, by hydrogenation if R8 is a benzyl group, or with fluoride anion such as tetrabutylammonium fluoride, if R is a trialkylsilyl group. The compound of formula 6 corresponds to the compound of formula 1 wherein R8 is H. Scheme 2 illustrates a process for preparing the compounds of the present invention by introducing the R11 group in one of the first stages in the synthesis of the final compounds. In step 1 of scheme 2, a halogen group R11 can be introduced according to a process substantially the same as that described for scheme 1 above. In step 2 of scheme 2, the compound of formula 9 can be prepared by treating the compound of formula 8 with a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 1, 1 '- carbonyldiimidazole (CDI) in methylene chloride. Treatment of the compound of formula 9 with hydrazine in acetonitrile at about 60 ° C provides the cyclic carbazate of formula 10. Treatment of the compound of formula 10 with O-alkylhydroxyamine in ethanol gives the oxime of formula 11. If desired, an amination reductive with an appropriate aldehyde of formula R2-C (O) H and deprotection of the hydroxy group at C-2 ', provides the compound of formula 12 which corresponds to a compound of formula 1 wherein X1 is -NH- and X2 is = NOR1. The compound of formula 10 can also be converted to a compound of formula 14 wherein X 1 is -NH-, as indicated in step 4 'of scheme 2 above, treating the compound of formula 10 with an appropriate heterocycle, such as a substituted imidazole, and a, β-unsaturated aldehyde such as acrolein in acetic acid, followed by reduction with sodium borohydride.
Scheme 3 illustrates the preparation of the compounds of formula 13, which correspond to the compounds of formula 1 in which X2 is = 0. In this procedure, the compound of formula 9 can be prepared as described above. The compound of formula 9 can be converted into the compound of formula 13 wherein X1 is O, CR4R5 or NR4, by treating the compound of formula 9 with NH2-X1-R2, where X1 O, CR4R5 or NR4 are. The compounds of the present invention can have asymmetric carbon atoms. Such mixtures of diastereomers can be separated into their individual diastereomers based on their physicochemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The enantiomers can be separated by converting the enantiomer mixtures into a mixture of diastereomers by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (e.g., by hydrolysis) the individual diastereomers to the pure enantiomers. corresponding. Such isomers, including mixtures of diastereomers and pure enantiomers, are all considered part of the invention. The compounds of formula 1 which are basic in nature can form a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the latter into the compound free base by treatment with an alkaline reagent, and then converting the above free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid, in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated in a solution of the free base in an organic solvent, by adding an appropriate mineral or organic acid to the solution. The compounds of formula 1 which are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the sodium and potassium salts. These salts can be prepared by conventional techniques. The chemical bases which are used as reagents for preparing the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula 1. Such non-toxic base salts include those derived from pharmacologically acceptable cations such such as sodium, potassium, calcium, magnesium and the like. These salts can be easily prepared by treating the 8
corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alkanol solutions of the acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as indicated above. In any case, stoichiometric amounts of the reagents are preferably employed to ensure that the reaction is completed and that the maximum yields of the desired final product are obtained. The activity of the compounds of the present invention against bacterial and protozoan pathogens is demonstrated by the ability of the compounds to inhibit the development of defined strains of human pathogens (test I) or animals (tests II and III).
Assay I Assay I, described below, employs conventional methodology and interpretation criteria and is designed to provide guidelines for chemical modifications that can lead to compounds that circumvent defined mechanisms of macrolide resistance. In trial I, a group of bacterial strains is assembled, including a diversity of target pathogenic species, including representatives of mechanisms of resistance to macrolides that have been characterized. The use of this group allows to establish the chemical structure / activity relation with respect to the pharmacological potency, spectrum of activity and structural elements or modifications that may be necessary to circumvent the mechanisms of resistance. The bacterial pathogens included in the tracking group are shown in the following table. In many cases, both the macrolide sensitive parental strain and the macrolide resistance strain derived therefrom are available to provide a more accurate assessment of the ability of the compounds to circumvent the resistance mechanism. The strains containing the gene with the name ermAIermB / ermC are resistant to antibiotics macrolides, lincosamides and streptogramin B, due to modifications (methylation) of the 23S rRNA molecules by an Erm methylase, which usually prevents the binding of the three structural classes. Two types of macrolide expulsion have been described; srA encodes a component of an expulsion system in staphylococci that prevents the entry of macrolides and streptogramins, while mefA / E encodes a transmembrane protein that seems to expel only macrolides. Inactivation of macrolide antibiotics can occur and can be induced by 2'-hydroxyl phosphorylation (mph) or by cleavage of macrocyclic lactone (esterase). The strains can be characterized using the conventional technology of chain reaction with polymerase (PCR) and / or by sequencing the determinant of resistance. The use of PCR technology in this application is described in J. Sutcliffe et al., "Detection of Erythromycin-Resistant Determinants by PCR", Antimicrobial Agents and Chemotherapy, 40 (11), 2562-2566 (1996). The assay is performed in microtiter trays and is interpreted in accordance with the standards Preformance Standards for Antimicrobial Disk Susceptibility Tests - Sixth Edition; Approved Standard, published by The National Committee for Clinical Laboratory Standards (NCCLS); To compare the strains, the minimum inhibitory concentration (MIC) is used. The compounds are initially dissolved in dimethylsulfoxide (DMSO) as stock solutions 40 mg / ml.
Assay II is used to assay activity against Pasteurella multocida and assay III is used to assay activity against Pasteurella haemolytica.
Test II This test is based on the method of dilution with liquids in microliter format. A single colony of P. multocida (strain 59A067) is inoculated into 5 ml of brain-heart infusion broth (BHI). The test compounds are prepared by solubilizing 1 mg of the compound in 125 μl of dimethyl sulfoxide (DMSO). Dilutions of the test compound are prepared using uninoculated BHI broth. The concentrations of test compound used range from 200 μg / ml to 0.098 μg / ml in serial dilutions in half. The BHI inoculated with P. multocida is diluted with non-inoculated BHI broth to obtain a suspension of 104 cells per 200 μl. The cell suspensions in BHI are mixed with the respective serial dilutions of the test compound and incubated at 37 ° C for 8 hours. The minimum inhibitory concentration (MIC) is equal to the concentration of the compound that exhibits a 100% inhibition of the development of P. multocida, as determined by comparison with a non-inoculated control.
Test lll This assay is based on the agar dilution procedure using a Steers replicator. Two to five colonies isolated from an agar plate in BHI broth are inoculated and incubated overnight at 37 ° C with shaking (200 rpm). The next morning, 300 μl of the fully grown P. haemolytica culture is inoculated into 3 ml of fresh BHI broth and the mixture is incubated at 37 ° C with shaking (200 rpm). The appropriate amounts of the test compounds are dissolved in ethanol and a series of serial dilutions are prepared in half. Two ml of the respective serial dilution are mixed with 18 ml of molten BHI agar and solidified. When the inoculated P. Haemolytica culture reaches a standard McFarland density of 0.5, approximately 5 μl of the P. haemolytica culture is inoculated onto BHI agar plates containing the various concentrations of the test compound using a Steers Replicator and incubated for 18 hours at 37 ° C. The initial concentrations of the test compound vary from 100 to 200 μg / ml. The MIC is equal to the concentration of the test compound which shows a 100% inhibition of the development of P. haemolytica, as determined by comparison with a non-inoculated control. The in vivo activity of the compounds of formula 1 can be determined by conventional animal protection studies well known to those skilled in the art, usually carried out in mice. The mice are divided into cages (10 per cage) after arrival and allowed to acclimate for a minimum of 48 hours before being used. The animals are inoculated with 0.5 ml of a bacterial suspension of 3x103 colony-forming units (CFU / ml) (strain 59A006 of P. multocida) intraperitoneally. Each experiment has at least three non-medicated control groups that include one infected with a 0.1X inoculation dose and two infected with a 1X inoculation dose; a data set of a 10X inoculation was also used. In general, all mice can be inoculated in a given study over a period of 30 to 90 minutes, especially if a repeating syringe (such as a Comwall® syringe) is used to administer the inoculation dose. Thirty minutes after beginning the inoculation, the first treatment with compound is administered. It may be necessary for a second person to start dosing the compound if all the animals have not yet been inoculated at the end of the thirty minute period. The routes of administration are subcutaneous or oral doses. Subcutaneous doses were administered to the flaccid skin of the back of the neck, while oral doses were administered via a feeding needle. In both cases, a volume of 0.2 ml per mouse is used. The compounds are administered 30 minutes, 4 hours and 24 hours after inoculation. A control compound of known efficacy administered by the same route is included in each assay. The animals are observed daily and the number of survivors in each group is noted. The control of the P. multocida model continues for 96 hours (four days) after inoculation.
PD50 is a calculated dose at which the test compound protects 50% of a group of mice from mortality due to bacterial infection, which would be fatal in the absence of drug treatment. The compounds of formula 1, and the pharmaceutically acceptable salts and solvates thereof (hereinafter "the active compounds"), can be administered orally, parenterally, topically or rectally, in the treatment or prevention of bacterial or protozoal infections. In general, these compounds are administered in the most desirable manner in doses ranging from about 0.2 mg per kg of body weight and per day (mg / kg / day) to about 200 mg / kg / day in a single dose or in doses divided (ie, from 1 to 4 doses per day) although variations will necessarily occur depending on the species, weight and condition of the subject to be treated and the particular administration route chosen. However, it is most desirable to employ a dosage level that is in the range of about 4 mg / kg / day to about 50 mg / kg / day. However, variations will occur depending on the species of mammal, fish or bird to be treated and their individual response to said medication, as well as the type of pharmaceutical formulation chosen and the period of time and interval in which said administration is performed. In some cases, lower dosage levels than the lower limit of the range mentioned above may be more than adequate, while, in other cases, even higher doses may be employed without causing any untoward side effects, provided that such larger doses are first divided into several small doses to be administered throughout the day. The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by the routes indicated above and such administration can be carried out in a single dose or in multiple doses. More particularly, the active compounds can be administered in a wide variety of different dosage forms, that is, they can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, tablets, dragees, hard candies, powders, sprays, creams, ointments , suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such vehicles include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, oral pharmaceutical compositions can be conveniently sweetened and / or flavored. In general, the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, together with various disintegrants such as starch (and preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for forming tablets. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; also including the preferred materials in this respect lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active compound may be combined with various sweetening or flavoring agents, coloring materials or pigments and, if desired, emulsifying and / or suspending agents, together with diluents such as water. , ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, solutions of an active compound in sesame or peanut oil or in aqueous propylene glycol can be employed. Aqueous solutions should be suitably buffered (preferably with pH greater than 8) if necessary and the liquid diluent should first be made isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by conventional pharmaceutical techniques well known to those skilled in the art.
In addition, it is also possible to administer the active compounds of the present invention topically and this can be done by means of creams, jellies, gels, pastes, patches, ointments and the like, in accordance with conventional pharmaceutical practice. For administration to animals other than humans, such as cattle or domestic animals, the active compounds can be administered in animal feed or orally in the form of potions. The active compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. The active compounds can also be associated with soluble polymers, such as targetable drug vehicles. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenyl, polyhydroxyethylaspartamide-phenol or poly (ethylene oxide) -silylisine substituted with palmitoyl moieties. In addition, the active compounds can be associated with a class of biodegradable polymers useful for achieving the controlled release of a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. The following examples illustrate specific embodiments of the invention, although the scope of the invention will not be limited to the examples presented in a specific manner. The following example illustrates a specific embodiment of the invention, although the scope of the invention will not be limited to the example presented specifically. In the following example, "Ac" represents an acetyl group, "Me" represents a methyl group and "Et" represents an ethyl group.
EXAMPLE 1
At -78 ° C, 1.74 ml of 0.5 M solution of KHMDS in toluene (0.87 mmol) was added to a solution containing the above compound of formula (in which "Ac" represents an acetyl group) (513). mg, 0.58 mmole) in 5.8 ml of DMF. After 30 minutes of stirring at -78 ° C, SELECTFLUOR ™ (sold by Air Products and Chemicals, Inc., Allentown, Pennyslvania, United States of America) (236 mg, 0.87 mmol) was added to this solution. After stirring for 30 minutes at -78 ° C, the new SELECTFLUOR ™ (27 mg, 0.076 mmol) was added. After a further 30 minutes of stirring at the same temperature, the reaction mixture was diluted with EtOAc (ethyl acetate) and washed with water and brine. It was dried over sodium sulfate and the solvent was removed giving 477 mg (93%) of a compound corresponding to formula 31 above, except that it had the hydroxy group of C-2 'protected with an acetyl group. This material was dissolved in 50 ml of MeOH and heated to 50 ° C overnight. Evaporation of the solvent and chromatography on SiO2 yielded the compound of formula 31 (corresponding to the compound of formula 2 cited above in which R12, R13, R14 and R15 are each H); NMR (CDCl 3, d) 8.93 (1 H, d), 8.42 (1 H, dd), 8.04 (1 H, dd), 7.57 (1 H, s), 7.35 (1 H, d), 7.24 (1 H , dd), 6.13 (1 H, s), 4.89 (1 H, dd), 4.28 (1 H, d), 4.19 (2 H, m), 4.07 (1 H, d), 3.69 (3 H, s), 3.66 (1 H, s), 3.56 (1 H, m), 3.48 (1 H, m), 3.41 (1 H, m), 3.24 (1 H, m), 2.76 (1 H, m), 2.60 ( 2H, m), 2.57 (3H, s), 2.36 (6H, s), 1.93 (2H, m), 1.74 (3H, d), 1.76-1.20 (6H, m), 1. 49 (3H, s), 1 .34 (3H, s), 1 .27 (3H, d), 1.22 (3H, d), 1 .1 1 (3H, d), 0.98 (3H, d), 0.83 (3H, t).
EXAMPLE 2
Following the procedures described in scheme 2 above, a compound corresponding to formula 1 was prepared, wherein X1 is -CH (CH3) (CH2) 2-, X2 is = NOCH3, R8 is H, R9 is CH3, R10 is CH2CH3, R11 is F and R12 is 4- (pyridin-3-yl) -imidazol-1-yl. MS 874 (M + 1).
32
The following examples, each having a structure according to formula 32 above, were prepared following the following procedure, which describes the preparation of the compound of Example 3. Examples 4 to 10 were prepared using the same procedure and using an appropriate heterocyclic compound instead of phenylimidazole.
EXAMPLE 3
12.7 μl of 90% acrolein (0.171 mmol) was added to a solution of compound 10 (100 mg, 0.155 mmol) and phenylimidazole (67.0 mg, 0.465 mmol) in 1.5 ml of acetic acid. The resulting mixture was stirred at room temperature overnight. Sodium cyanoborohydride (46.7 mg, 0.775 mmole) was then added and the solution was stirred at room temperature overnight. The solution was diluted with water and its pH adjusted to 10 with 40% aqueous NaOH solution. The aqueous solution was extracted with methylene chloride. The combined methylene chloride layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by TLC (thin layer chromatography) (89% methylene chloride-10% methanol-1% ammonium hydroxide), affording 6 mg (5% yield) of Example 3.
Claims (9)
1. - A compound of formula or one of the pharmaceutically acceptable salts or solvates thereof, wherein: X1 is O, -CR4R5- or -NR4-; X2 = 0 u = N0R1-; R1 is H or C1-C0 alkyl, with 1 to 3 carbon atoms of said alkyl optionally replaced by a heteroatom selected from 0, S and -N (R4) -. and said alkyl being optionally substituted with 1 to 3 substituents independently selected from the group consisting of -C- (0) O (C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halogen, nitro, cyano, 4-heterocyclyl to 10 members, C1-C10 alkyl, -NR4R5, C6-C aryl, or -S (0) n (C1-C10 alkyl), where n is an integer ranging from 0 to 2 and -SO2NR4R5; R2 is - (CR4R5) p (4- to 10-membered heterocycle) or - (C-R4R5) n (C6-C6 aryl), where n is an integer from 0 to 6, being from 1 to 3 R4 groups or R5 of the - (CR4R5) n- portion of the above R2 groups optionally substituted with a halogen substituent, and the heterocyclic and aryl portions of the above R groups being optionally substituted with 1 to 4 R3 groups; each R3 is independently selected from halogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, alkoxy CI-CT, Ci-C-io alkyl, C2-Ce alkenyl, C -Ce alkynyl, -C (0) R6, - C (0) 0R6, -OC (0) R6, -NR6C (0) R7 -NR6C (0) NR1R7 -NR6C (0) OR7 -C (0) NR6R7, -NR6R7 -NR6OR7, -S02-NR6R7, -S - (0) j (C? -C? Alkyl), where j is an integer from 0 to 2, - (CR1 R2) t (C3-C? O aryl), - (CR4R5) t (4- to 10-membered heterocycle) ), - (CR4R5) qC (0) (CR4R5) t (aryl Ce-Cio), - (CR4R5) qC (0) - (CR4R5) t (heterocycle of 4 to 10 members), - (CR4R5) tO (CR4R5) ) q (aryl Ce-Cio), - (CR4R5) tO (CR4R5) q (heterocycle of 4 to 10 members), (CR4R5) qS02 (CR4R5) t (AriIo Ce-Cio) and - (CR4R5) q-S02 (CR4R5) t (heterocycle of 4 to 10 members), each of q and t being, independently, an integer from 0 to 5 wherein 1 or 2 ring carbon atoms of the heterocyclic portions of the above R 10 groups are optionally substituted with an oxo portion (= O) and the alkyl, alkenyl, alkynyl, aryl and heterocyclic portions of the above R 0 groups being optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR6, -C (0) R6, -C (0) OR6, -0C (0) R6 -NR6C (0) R7 - C (0) NR6R7, -N-RdR7, -NR60R7, C?-Cß alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, - (CR 4 R 5) t (aryl Ce-Cι) and - (CR R 5) t (heterocycle of 4 to 10 members), where t is an integer 0 to 5, each of R 4 and R 5 is independently selected from H and C 1 -C 6 alkyl; each of Rd and R7 is independently selected from H, C -C6 alkyl, - (CR4R5) t (aryI Ce-Cio), and - (CR4R5) t- (heterocyclic from 4 to 10 members), where t is an integer of 0 to 5, with 1 or 2 ring carbon atoms of the heterocyclic group being optionally substituted with an oxo portion (= 0), and the alkyl, aryl and heterocyclic portions of the above Rβ and R7 groups being optionally substituted with 1 to 3 substituents , independently selected from halogen, cyano, nitro, NR4R5, trifluoromethyl, trifluoromethoxy, Ci-Cß alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy and C?-C6 alkoxy; R8 is H, -C (0) (C 1 -C 5 alky), benzyl, benzyloxycarbonyl or (C 1 -C 6 alkyl) 3-Silyl; R9 is C? -C6 alkyl; R10 is H or C1-C10 alkyl; and R11 is selected from chlorine, bromine, iodine, fluoro and cyano; with the proviso that when X2 is = 0, then R11 is cyano, or from 1 to 3 of the groups R4 or R5 of the - (CR4-R5) n- portion of the R2 groups mentioned above are alkyl d-Ce or they are replaced by a halogen substituent.
2 - A compound of formula or one of the pharmaceutically acceptable salts or solvates thereof, wherein each of R12, R13, R14 and R15 is independently selected from H, halogen, methyl and ethyl.
3. A compound according to claim 2, further characterized in that R14 and R15 are both H and each of R12 and R13 is independently selected from H and methyl.
4. A compound according to claim 2, further characterized by each of R12. R13 R14 and R15 is H.
5.- A compound of formula or one of the pharmaceutically acceptable salts or solvates thereof, wherein each of R12, R13, R14 and R15 is independently selected from H, halogen, methyl and ethyl, with the proviso that at least one of R12, R13, R14 and R15 are not H.
6. - A compound according to claim 5, further characterized in that R14 and R15 are both H, R12 is methyl and R13 is selected from H and methyl.
7. A pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, Or a disorder related to a bacterial infection or a protozoal infection in a mammal, fish or bird, comprising a therapeutically effective amount of a compound according to claim 1, and a pharmaceutically acceptable carrier.
8.- The use of a compound in accordance with the claim 1 for the preparation of a medicament for treating a selected disorder of a bacterial infection, a protozoal infection, or a disorder related to a bacterial infection or a protozoal infection in a mammal, fish or bird.
9. A process for preparing a compound according to claim 1, further characterized in that R11 is a halogen group, which comprises treating a compound of formula wherein R8, R9, R10, X1, X2 and R2 are as defined in claim 1, with a halogenating agent.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/117,342 | 1999-01-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA01007584A true MXPA01007584A (en) | 2002-05-09 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2359708C (en) | Ketolide antibiotics | |
US6664238B1 (en) | Carbamate and carbazate ketolide antibiotics | |
HRP980571A2 (en) | 9-amino-3-keto erythromycin derivatives | |
HRP980316A2 (en) | 9-oxime erythromycin derivatives | |
EP1132392B1 (en) | Ketolide antibiotics | |
JP3839246B2 (en) | New macro ride | |
EP1114826A2 (en) | Novel antibacterial and prokinetic macrolides | |
EP1167376B1 (en) | Macrolide antibiotics | |
JP2001348397A (en) | Erythromycin a derivative | |
HRP980248A2 (en) | Erythromycin derivatives | |
EP1115732B1 (en) | Carbamate and carbazate ketolide antibiotics | |
US20020077302A1 (en) | Tricyclic erythromycin derivatives | |
US20020151507A1 (en) | 9-oxime erythromycin derivatives | |
US20020061856A1 (en) | Novel tricyclic erythromycin derivatives | |
MXPA01007584A (en) | Ketolide antibiotics | |
MXPA01002355A (en) | Ketolide antibiotics | |
EP1298138B1 (en) | Carbamate and Carbazate Ketolide Antibiotics | |
MXPA00011389A (en) | New macrolide | |
EP1749832A2 (en) | Carbamate and carbazate ketolide antibiotics |