MXPA98009307A - Erythromycines replaced in 6-0- and method to do - Google Patents
Erythromycines replaced in 6-0- and method to doInfo
- Publication number
- MXPA98009307A MXPA98009307A MXPA/A/1998/009307A MX9809307A MXPA98009307A MX PA98009307 A MXPA98009307 A MX PA98009307A MX 9809307 A MX9809307 A MX 9809307A MX PA98009307 A MXPA98009307 A MX PA98009307A
- Authority
- MX
- Mexico
- Prior art keywords
- compound
- formula
- substituted
- alkyl
- previously defined
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 464
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000011780 sodium chloride Substances 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 206010060945 Bacterial infection Diseases 0.000 claims abstract description 16
- 150000002148 esters Chemical class 0.000 claims abstract description 13
- 239000000651 prodrug Substances 0.000 claims abstract description 12
- 229940002612 prodrugs Drugs 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 175
- 125000001072 heteroaryl group Chemical group 0.000 claims description 110
- -1 (i) -O- Chemical class 0.000 claims description 103
- 125000003118 aryl group Chemical group 0.000 claims description 93
- 229910052739 hydrogen Inorganic materials 0.000 claims description 90
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 87
- 239000001257 hydrogen Substances 0.000 claims description 81
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 77
- 239000000203 mixture Substances 0.000 claims description 67
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 63
- 125000003107 substituted aryl group Chemical group 0.000 claims description 58
- 229910021481 rutherfordium Inorganic materials 0.000 claims description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 48
- 125000001424 substituent group Chemical group 0.000 claims description 46
- 229910052702 rhenium Inorganic materials 0.000 claims description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 18
- 239000002168 alkylating agent Substances 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 239000003937 drug carrier Substances 0.000 claims description 16
- 125000004043 oxo group Chemical group O=* 0.000 claims description 16
- 125000004429 atoms Chemical group 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 claims description 14
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 13
- 241000124008 Mammalia Species 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 230000001276 controlling effect Effects 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000003120 macrolide antibiotic agent Substances 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- HUCVOHYBFXVBRW-UHFFFAOYSA-M Caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 10
- YORCIIVHUBAYBQ-UHFFFAOYSA-N Propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 10
- 239000000010 aprotic solvent Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 229910052703 rhodium Inorganic materials 0.000 claims description 10
- AGEZXYOZHKGVCM-UHFFFAOYSA-N Benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 9
- 150000002923 oximes Chemical class 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 8
- JTLAIKFGRHDNQM-UHFFFAOYSA-N 1-bromo-2-fluoroethane Chemical compound FCCBr JTLAIKFGRHDNQM-UHFFFAOYSA-N 0.000 claims description 8
- AVMHMVJVHYGDOO-UHFFFAOYSA-N 1-bromobut-2-ene Chemical compound CC=CCBr AVMHMVJVHYGDOO-UHFFFAOYSA-N 0.000 claims description 8
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 claims description 8
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 claims description 8
- MONMFXREYOKQTI-UHFFFAOYSA-M 2-bromopropanoate Chemical compound CC(Br)C([O-])=O MONMFXREYOKQTI-UHFFFAOYSA-M 0.000 claims description 8
- RUROFEVDCUGKHD-UHFFFAOYSA-N 3-bromoprop-1-enylbenzene Chemical compound BrCC=CC1=CC=CC=C1 RUROFEVDCUGKHD-UHFFFAOYSA-N 0.000 claims description 8
- QJQXVPCIRZUOIP-UHFFFAOYSA-N 4-(bromomethyl)quinoline Chemical compound C1=CC=C2C(CBr)=CC=NC2=C1 QJQXVPCIRZUOIP-UHFFFAOYSA-N 0.000 claims description 8
- LHMHCLYDBQOYTO-UHFFFAOYSA-N Bromofluoromethane Chemical compound FCBr LHMHCLYDBQOYTO-UHFFFAOYSA-N 0.000 claims description 8
- LIGACIXOYTUXAW-UHFFFAOYSA-N Phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 claims description 8
- 238000003386 deoximation reaction Methods 0.000 claims description 8
- BRLQWZUYTZBJKN-UHFFFAOYSA-N epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 8
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- FTBPZRNURKMEFD-ONEGZZNKSA-N (E)-1-bromopent-2-ene Chemical compound CC\C=C\CBr FTBPZRNURKMEFD-ONEGZZNKSA-N 0.000 claims description 7
- KQNBRMUBPRGXSL-UHFFFAOYSA-N 1-(bromomethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1 KQNBRMUBPRGXSL-UHFFFAOYSA-N 0.000 claims description 7
- GIGRWGTZFONRKA-UHFFFAOYSA-N 1-(bromomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CBr)C=C1 GIGRWGTZFONRKA-UHFFFAOYSA-N 0.000 claims description 7
- CCXQVBSQUQCEEO-UHFFFAOYSA-N 1-bromobutan-2-one Chemical compound CCC(=O)CBr CCXQVBSQUQCEEO-UHFFFAOYSA-N 0.000 claims description 7
- NJWIMFZLESWFIM-UHFFFAOYSA-N 2-(chloromethyl)pyridine Chemical compound ClCC1=CC=CC=N1 NJWIMFZLESWFIM-UHFFFAOYSA-N 0.000 claims description 7
- BHELZAPQIKSEDF-UHFFFAOYSA-N Allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 7
- JPOXNPPZZKNXOV-UHFFFAOYSA-N Bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 claims description 7
- HGLBFWLVLORTTN-UHFFFAOYSA-M C(CCC)OCS(=O)(=O)[O-] Chemical compound C(CCC)OCS(=O)(=O)[O-] HGLBFWLVLORTTN-UHFFFAOYSA-M 0.000 claims description 7
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 claims description 7
- DNPRVXJGNANVCZ-UHFFFAOYSA-N bromo(nitro)methane Chemical compound [O-][N+](=O)CBr DNPRVXJGNANVCZ-UHFFFAOYSA-N 0.000 claims description 7
- SKIMEKUYIQHJQV-UHFFFAOYSA-N bromomethylsulfonylbenzene Chemical compound BrCS(=O)(=O)C1=CC=CC=C1 SKIMEKUYIQHJQV-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 230000000875 corresponding Effects 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 7
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 7
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- JWQMKMSVOYQICF-UHFFFAOYSA-N 1,3-dibromoprop-1-ene Chemical compound BrCC=CBr JWQMKMSVOYQICF-UHFFFAOYSA-N 0.000 claims description 6
- CNQCWYFDIQSALX-UHFFFAOYSA-N 3-(chloromethyl)pyridine Chemical compound ClCC1=CC=CN=C1 CNQCWYFDIQSALX-UHFFFAOYSA-N 0.000 claims description 6
- PCLBCJBFJNJWHS-UHFFFAOYSA-N 3-(trifluoromethoxy)propylbenzene Chemical compound FC(F)(F)OCCCC1=CC=CC=C1 PCLBCJBFJNJWHS-UHFFFAOYSA-N 0.000 claims description 6
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N Benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- CCAFPWNGIUBUSD-UHFFFAOYSA-N Diethyl sulfoxide Chemical compound CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 claims description 6
- GNOIPBMMFNIUFM-UHFFFAOYSA-N Hexamethylphosphoramide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 125000005842 heteroatoms Chemical group 0.000 claims description 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 229910052701 rubidium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 6
- LNNXOEHOXSYWLD-UHFFFAOYSA-N 1-bromobut-2-yne Chemical compound CC#CCBr LNNXOEHOXSYWLD-UHFFFAOYSA-N 0.000 claims description 5
- QIIWWNIGGARHKV-UHFFFAOYSA-N 3-bromoprop-1-enylsulfonylbenzene Chemical compound BrCC=CS(=O)(=O)C1=CC=CC=C1 QIIWWNIGGARHKV-UHFFFAOYSA-N 0.000 claims description 5
- WZIYCIBURCPKAR-UHFFFAOYSA-N 4-(chloromethyl)pyridine Chemical compound ClCC1=CC=NC=C1 WZIYCIBURCPKAR-UHFFFAOYSA-N 0.000 claims description 5
- HRZFUMHJMZEROT-UHFFFAOYSA-L 7681-57-4 Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 5
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- RWPGFSMJFRPDDP-UHFFFAOYSA-L Potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- JVBXVOWTABLYPX-UHFFFAOYSA-L Sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 5
- AAPLIUHOKVUFCC-UHFFFAOYSA-N Trimethylsilanol Chemical compound C[Si](C)(C)O AAPLIUHOKVUFCC-UHFFFAOYSA-N 0.000 claims description 5
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 claims description 5
- 230000002411 adverse Effects 0.000 claims description 5
- FGRVOLIFQGXPCT-UHFFFAOYSA-L dipotassium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound [K+].[K+].[O-]S([O-])(=O)=S FGRVOLIFQGXPCT-UHFFFAOYSA-L 0.000 claims description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
- OCFVSFVLVRNXFJ-UHFFFAOYSA-N potassium hydride Inorganic materials [H-].[K+] OCFVSFVLVRNXFJ-UHFFFAOYSA-N 0.000 claims description 5
- 229940043349 potassium metabisulfite Drugs 0.000 claims description 5
- 235000010263 potassium metabisulphite Nutrition 0.000 claims description 5
- CBMSDILKECEMOT-UHFFFAOYSA-N potassium;2-methylpropan-1-olate Chemical compound [K+].CC(C)C[O-] CBMSDILKECEMOT-UHFFFAOYSA-N 0.000 claims description 5
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 5
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 5
- 235000011152 sodium sulphate Nutrition 0.000 claims description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical class S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 claims description 5
- JXAZAUKOWVKTLO-UHFFFAOYSA-L Sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 claims description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229940079827 sodium hydrogen sulfite Drugs 0.000 claims description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 4
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 claims description 4
- 229910052721 tungsten Inorganic materials 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 3
- CSMWJXBSXGUPGY-UHFFFAOYSA-L Sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 claims description 3
- 229940075931 sodium dithionate Drugs 0.000 claims description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- UMLFTCYAQPPZER-UHFFFAOYSA-N 4-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=C(C#N)C=C1 UMLFTCYAQPPZER-UHFFFAOYSA-N 0.000 claims description 2
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 claims description 2
- 229940075933 dithionate Drugs 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L Sulphite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims 1
- 230000000845 anti-microbial Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 40
- 239000011541 reaction mixture Substances 0.000 description 35
- 229940076185 Staphylococcus aureus Drugs 0.000 description 26
- 241000191967 Staphylococcus aureus Species 0.000 description 26
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 26
- 235000011114 ammonium hydroxide Nutrition 0.000 description 26
- 229940055023 Pseudomonas aeruginosa Drugs 0.000 description 24
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 24
- 239000000908 ammonium hydroxide Substances 0.000 description 24
- 241000588724 Escherichia coli Species 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 229940076156 Streptococcus pyogenes Drugs 0.000 description 15
- 241000193996 Streptococcus pyogenes Species 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 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 14
- 230000000844 anti-bacterial Effects 0.000 description 14
- 239000002131 composite material Substances 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 12
- 239000012267 brine Substances 0.000 description 11
- 229940079593 drugs Drugs 0.000 description 11
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 10
- 229960003276 erythromycin Drugs 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 9
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- SUMDYPCJJOFFON-UHFFFAOYSA-M isethionate Chemical compound OCCS([O-])(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-M 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M isothiocyanate Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000000468 ketone 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
- POULHZVOKOAJMA-UHFFFAOYSA-M laurate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000006210 lotion 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
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 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
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M methanoate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- SOHCYNFHNYKSTM-UHFFFAOYSA-N methylsulfinylmethane;oxolane Chemical compound CS(C)=O.C1CCOC1 SOHCYNFHNYKSTM-UHFFFAOYSA-N 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 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
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- MKQLBNJQQZRQJU-UHFFFAOYSA-N morpholin-4-amine Chemical group NN1CCOCC1 MKQLBNJQQZRQJU-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 230000000269 nucleophilic Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000000668 oral spray Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atoms Chemical group O* 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000011528 polyamide (building material) Substances 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 125000003373 pyrazinyl 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
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- VQOIVBPFDDLTSX-UHFFFAOYSA-M sodium;3-dodecylbenzenesulfonate Chemical compound [Na+].CCCCCCCCCCCCC1=CC=CC(S([O-])(=O)=O)=C1 VQOIVBPFDDLTSX-UHFFFAOYSA-M 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 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
- 239000001384 succinic acid Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
- 235000008170 thiamine pyrophosphate Nutrition 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical group CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical class CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Abstract
Antimicrobial compounds having the formula (II), (III), (IV), (V), (VI), (VII), (VIII), and (IX) as well as the salts, esters and pro-drugs thereof pharmaceutically acceptable, pharmaceutical compositions comprising such compounds, methods of treating bacterial infections by the administration of such compounds, and processes for the preparation of the compounds
Description
ERYTHROMOCINES SUBSTITUTED IN 6-0 AND METHOD TO MAKE THEM
TECHNICAL FIELD The present invention relates to novel semisynthetic macrolides having antibacterial activity and useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to 6-O substituted erythromycin derivatives, compositions containing such compounds and methods for using same, as well as processes for making such compounds.
BACKGROUND OF THE INVENTION Erythromycins A to D, represented by the formula (I),
(I)
They are well known and potent antibacterial agents, widely used to treat and prevent bacterial infections. As with other antibacterials, however, they have been identified as strains of b a cte r i a- that J
they have insufficient resistance or susceptibility to erythromycin. Also, erythromycin A has only a weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds having improved antibacterial activity, having less potential to develop resistance, having the desired Gram-negative activity, or having unexpected selectivity against target microorganisms. Consequently, numerous researchers have prepared chemical derivatives of erythromycin in an attempt to obtain analogs that have profiles of
modified or improved antibiotic activity. Morimoto et al. , described the preparation of 6-O-methyl erythromycin A in J. Antibiotics 37: 187 (1984). Morimoto et al. , furthermore, deciphers a series of derivatives of O-alkyl erythromycin A in J. Antibiotics 43: 286 (1990). In his experience, "alkylation in -O, different from methylation, has
place in the hydroxyl group of C-1 only. However, in European Patent Application 272, 11, published on June 22, 1988, Morimoto et al. , describe compounds of 6-0-C? -C3-alkyl erythromycin A. In European Patent Application 215,355, published on March 28, 1987, Omura and Itoh describe 6-O-lower alkyl erythromycins as
stimulants of gastrointestinal contractile movements.
BRIEF DESCRIPTION OF THE INVENTION The present invention provides a novel class of 6-0 substituted erythromycin compounds which possess antibacterial activity.
In one aspect of the present invention a novel erythromycin-substituted 6-O- compound selected from the formulas: OD; (10); (IV);
(V);
(SAW);
(vp);
(HIV);
(DO;
as the pharmaceutically acceptable salts, and their esters and pro-drugs. formulas (ll) - (IX) above, X is: (1) = 0 (2) = N-OH (3) = NO-R1 wherein R1 is (a) unsubstituted C? -C? 2 alkyl , (b) C 1 -C 2 alkyl substituted with aryl, (c) substituted d-C 12 alkyl with substituted aryl, (d) C 3 -Ci 2 cycloalkyl, (e) -Si- (R 11) (R 12) ( R13) wherein R11, R12 and R13 are each independently selected from C1-C12 alkyl, (f) -Si- (aryl) 3, or (4) = NOC (R9) (R10) -O-R1 wherein R 1 is as defined above and R 9 and R 10 are each independently selected from the group consisting of: (a) hydrogen, (b) unsubstituted C 1 -C 12 alkyl, (c) C 1 -C 12 alkyl substituted with aryl, (d) C 1 -C 12 alkyl substituted with substituted aryl, or R 9 and R 10 taken together with the carbon to which they are attached form a C 3 -C 12 cycloalkyl ring. Ra is hydrogen or hydroxy; Rb is hydrogen or hydroxy; one of Rc and Rd is hydrogen and the other of Rc and Rd is: (1) hydroxy, (2) protected hydroxy, (3) halogen, or (4) NR3R4 where R3 and R4 are independently selected from: (a) hydrogen, (b) C 1 -C 12 alkyl, (c) C 1 -C 12 alkyl substituted with aryl, (d) C 1 -C 12 alkyl substituted with substituted aryl, (e) C 1 -C 12 alkyl substituted with heteroaryl, and (f) substituted C 1 -C 12 alkyl with substituted heteroaryl, or (5) -SO 2 - (substituted C 1 -C 6 alkyl, or R 3 and R 4 taken together with the carbon to which they are attached form a heterocycloalkyl ring of 3-7 members, or R ° and Rd taken together are: (D = 0, (2) = N-OH, (3) = N-OR1 where R1 is as defined above; Rβ is methoxy, fluoride or hydroxy; Rf is hydrogen or a hydroxy protecting group; Rg is selected from the group consisting of: (1) unsubstituted C 1 -C 6 alkyl, (2) substituted alkyl with one or more substituents selected from the group consisting of: (a) aryl, (b) substituted aryl, ( c) heteroaryl, (d) substituted heteroaryl, (e) heteroarylalkyl, (f) hydroxy, (g) C? -C6 alkoxy, (h) NR3R4 wherein R3 and R4 are as defined above, and (i) - CH2-M-RS wherein M is selected from a group consisting of: (i) -O-, (ii) -NH-, (iii) -NMe-, (iv) -S (O) n- where n is 0, 1 or 2, (v) -NHC (= O) -, and (vi) -C (= O) -NH-, and R5 is selected from a group consisting of: (i) - (CH2 ) n-aryl where n is 0, 1 or 2, (ii) - (CH2) n-aryl substituted where n is 0, 1 or 2, (iii) - (CH2) n- heteroaryl where n = 0 , 1 or 2, (iv) - (CH2) n-substituted heteroaryl wherein n is 0, 1 or 2, and
(v) - (CH2) n-heteroarylalkyl wherein n is 0, 1 or 2, (3) C3-C12 cycloalkyl, (4) aryl, (5) substituted aryl, (6) heteroaryl, and (7) heteroaryl replaced; Rh is selected from the group consisting of: (a) hydrogen, (b) C 1 -C 6 alkyl, (c) substituted C 1 -C 4 alkyl, (d) substituted C 1 -C 4 alkyl with substituted heteroaryl; R is selected from the group consisting of: (1) Ci alkyl substituted with a substituent selected from the group consisting of: (a) F, (b) S (O) "R6 wherein n is 0, 1 or 2 and C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted with aryl, (c) NHC (O) R 6 wherein R 6 is as defined above, and (d) NHC (O) NR 3 R 4 wherein R 3 and R 4 are independently selected from hydrogen and C 1 -C 3 alkyl, (2) C 2 -C 0 alkyl 0; (3) C2-C10 alkyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C1-C3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 they are as previously defined,
(i) = NO-R6 wherein R6 is as previously defined, (j) -CN, (k) S (0) nR6 wherein n is 0, 1 or 2 and R6 is C1-C3 alkyl or alkyl of C1-C3 substituted with aryl, (I) aryl, (m) substituted aryl, (n) heteroaryl, (o) substituted heteroaryl, (p) C3-C7 cycloalkyl, (q) (heteroaryl) alkyl, (r) NHC (O) R6 wherein R6 is as previously defined, (s) NHC (O) NR3R4 where R3 and R4 are as previously defined, (t) = N-NR3R4 where R3 and R4 are as previously defined, (u) = N-NHC (O) R6 where R6 is as previously defined, and
(v) = N-NHC (O) NR3R4 wherein R3 and R4 are as previously defined; (4) C 2 -C 0 alkenyl; (5) C2-C10 alkenyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C1-C3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 they are as previously defined, (i) = NO-R6 where R6 is as previously defined, II
0) -CN, (k) S (O) nR6 where n is 0, 1 or 2 and R6 is d-C3 alkyl or d-Cs alkyl substituted with aryl, (I) aryl, (m) substituted aryl , (n) heteroaryl, (o) susbtituido heteroaryl, (p) C3-C7 cycloalkyl, (q) (heteroaryl) alkyl, (r) NHC (O) R6 where R6 is as previously defined, (s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N-NR3R4 wherein R3 and R4 are as previously defined, (u) = N-NHC (O) R6 where R6 is as previously defined, and (v) = N-NHC (O) NR3R4 wherein R3 and R4 are as previously defined; (6) Alkynyl of C2-C? 0; and (7) C -C10 Alkynyl substituted with one or more substituents selected from the group consisting of: (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) substituted heteroaryl; one of Y and Z is hydrogen and the other is selected from a group consisting of: (1) hydrogen, (2) hydroxy, (3) protected hydroxy, and (4) NR3R4 wherein R3 and R4 are as defined above; W is: (D -o-, (2) -NH-, (3) -NMe-, or (4) absent; A, B, D and E are, in each occurrence, independently selected from the group consisting of: (1) hydrogen, (2) unsubstituted C? -C alkyl, and (3) substituted C? -C6 alkyl with one or more substituents selected from the group consisting of: (a) aryl, (b) substituted aryl , (c) heteroaryl, (d) substituted heteroaryl, (e) heteroarylalkyl, (f) hydroxy, (g) C? -C6 alkoxy, (h) NR3-R4, wherein R3 and R4 are as defined above, e (i) -CHM-R5 wherein M is selected from a group consisting of: (i) -O-, (ii) -NH-, (iii) -NMe-, (iv) -S (O ) "- where n is 0, 1 or 2, (v) -NHC (= O) -, and (vi) -C (= O) -NH-, and R5 is selected from a group consisting of: ( i) - (CH2) p-aryl where n is 0, 1 or 2, (ii) - (CH2) n-aryl substituted where n is 0, 1 or 2, (iii) - (CH2) p-heteroaryl where n = 0, 1 or 2, (iv) - (CH2) n-substituted heteroaryl wherein n is 0, 1 or 2, and (v) - (CH2) n-heteroarylalkyl wherein n is 0, 1 or 2, or any pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7- membered ring optionally containing a hetero function selected from: (D -O-, (2) -S (O) n-, where n is 0, 1 or 2, (3) -NH-, (4) -N (CH3) -, and (5) -N (R5) - where R5 is like previously defined In another aspect of the present invention are described pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier and treatment of antibacterial infections with such compositions. they are also described. The compounds and compositions of the present invention have antibacterial activity. In a further aspect of the present invention there are provided processes for the preparation of 6-O- substituted macrolide derivatives of Formulas (II), (III), (IV), (V), (VI), (VII) , (VIII) and (IX) above.
DETAILED DESCRIPTION OF THE INVENTION One embodiment of the present invention comprises a compound of formula (II) above, wherein X, R, Ra, R, R °, Rd, Re and Rf are as defined above. Another embodiment of the present invention comprises a compound of the formula (III) above, wherein Y, Z, R, Ra, Rb, Rc, Rd, Re and Rf are as defined above. Another embodiment of the present invention comprises a compound of the formula (IV) above, wherein R, Rb, Rc, Rd, Ra and Rf are as defined above. Another embodiment of the present invention comprises a compound of the formula (V) above, wherein R, Rb, R °, Rd, Re and Rf are as defined above. Another embodiment of the present invention comprises a compound of the formula (VI) above, wherein R, Ra, Rb, Rc, Rd, Re and Rf are as defined above.
Another embodiment of the present invention comprises a compound of the formula (VII) above, wherein W, R, Rb, Rc. Rd, Rβ, Rf and R9 are as defined above. Another embodiment of the present invention comprises a compound of the formula (VIII) above, wherein A, B, D, E, R, Rb, Rc, Rd, Re and Rf are as defined above. Another embodiment of the present invention comprises a compound of the formula (IX) above, wherein A, B, D, E, R, Rb, Rc, Rd, Re, Rf and Rh are as defined above. A preferred embodiment of the present invention is the compound of the formula (X):
(X)
where X and R are as defined above. Another preferred embodiment of the present invention is the compound of the formula (XI): (XI)
where Y, Z and R are as defined above. A preferred intermediate in the preparation of the compound of the formula (X) is the compound of the formula (XII):
(XII)
wherein X is as defined above and Rp is a hydroxy protecting group.
Representative of the compounds of the invention include: Compound of the formula (X): X is = N-O- (l-isopropoxycyclohexyl), R is allyl;
Compound of formula (X): X is = O, R is allyl; Compound of formula (X): X is = O, R is propyl; Compound of the formula (X): X = O, R 2,3-dihydroxypropyl; Compound of the formula (X): X = O, R is 2,3-epoxypropyl Compound of the formula (X): X is = O, R is 2-hydroxy-3- (imidazol-1-yl) propyl; Compound of the formula (X): X is = O, R is 2-hydroxy-3- (morpholin-4-yl) propyl; Compound of formula (X): X is = O, R is 2-hydroxy-3- (benzylamino) propyl; Compound of the formula (X: X is = O, R is -CH2-CHO; Compound of the formula (X: X is = O, R is -CH2-C (O) -CH3; Compound of the formula (X: X is = 0, R is -CH2-C = CH; Compound of the formula (X: X is = O, R is -CH2-CHOH-CH2-N3; Compound of the formula (X: X is = O, R is -CH2-CH = N-OH; Compound of the formula (X: X is = O, R is -CH2-CH20H; Compound of the formula (X: X is = O, R is -CH2-CH2NH2; the formula (X: X is = O, R is -CH2-CN; Compound of the formula (X: X is = O, R is -CH-Phenyl; Compound of the formula (X: X is = 0, R is -CH2-CH = CH (Phenyl): Compound of the formula (X: X is = O, R is -CH2-CH = N-0-CH3; Compound of the formula (X: X is = O, R is - CH2-CH = NO-CH2-Phenyl; Compound of the formula (X: X is = 0, R is -CH2-CH = NN (CH3) 2; Compound of the formula (X: X is = O, R is - CH2-CH = N-NH (CH3): Compound of the formula (X: X is = O, R is -CH2-CH = N- (4-Morpholinyl);
Ormula (X): X is = O, R is -CH2-CH = N-NH (Phenyl); Ormula (X): X is = O, R is -CH2-CH = N-N (Phenyl) 2; Ormula (X): X is = O, R is -CH2CH2CH20H; Ormula (X): X is = O, R is -CH2-CO2H, ormula (X): X is = O, R is -CH2CH2NH (CH3); Ormula (X): X is = O, R is -CH2CH2NHCH2CH3; Ormula (X): X is = O, R is -CH2CH2NHCH2CH2-Phenyl; Ormula (X): X is = O, R is -CH2CH2N (CH3) 2; '(X): X is = O, R is -CH2CH2- (4-morpholinyl); Ormula (X): X is = O, R is -CH2C (O) NH2; Ormula (X): X is = O, R is -CH2NHC (O) NH2; order (X): X is = O, R is -CH2NHC (O) CH3; Ormula (X): X is = 0, R is -CH2F; Ormula (X) X is = O, R is -CH2CH2OCH3; Ormula (X) X is = O, R is -CH2CH3; Ormula (X) X is = O, R is -CH2CH = C (CH3) 23; Ormula (X) X is = O, R is -CH2CH = CHF; Ormula (X) X is = O, R is - (CH2) 3-F; Ormula (X) X is = O, R is - (CH2) 2-CH (CH3) 2; Ormula (X) X is = O, R is - (CH2) 2-O- (CH2) 2-O-CH3; Ormula (X) X is = O, R is -CH2-F; Ormula (X) X is = N-OH, R is -CH2-C --- CH; Ormula (X) X is = N-O-CH3, R is -CH2-C = CH; Ormula (X) X is = N-O-Benzyl, R is -CH2-C = CH; Ormula (X) X is = N-O-CH2-O-CH3, R is -CH2-C = CH;
Compound of the formula (X): X is = N-O-CH2-O-CH2-CH2-O-CH3, R is -CH2-C--.CH; Compound of the formula (X): X is = N-OH, R is -CH2-CH = CH2; Compound of the formula (X): X is = N-O-CH3, R is -CH2-CH = CH2; Compound of the formula (X): X is = N-O-Benzyl, R is -CH2-CH = CH2;
Compound of the formula (X): X is = N-O-CH2-O-CH3, -CH2-CH = CH2; Compound of the formula (X): X is = N-O-CH2-O-CH2-CH2-O-CH3) R is
CH2-CH = CH2; Compound of formula (XI): Y is NH2, Z is H, R is -CH2-C = CH; Compound of the formula (XI): Y is NH-CH2CH2CH3, Z is H, R is -CH2
C = CH; Compound of the formula (XI): Y is NH- (CH2) 9-CH3, Z is H, R is -CH2- C = CH; Compound of formula (XI): Y is NH-CH (CH3) 2, Z is H, R is -CH2-C = CH; Compound of the formula (XI): Y is I -piperidinyl, Z is H, R is -CH2-C = CH;
Compound of formula (XI): Y is H, Z is I -piperidinyl, R is -CH2-C = CH;
Compound of Formula (XI): Y is H, Z is NH2, R is CH2-C = CH; Compound of Formula (XI): Y is H, Z is NH-CH2CH2CH3, R is -CH2- C = CH; Compound of Formula (XI): Y is H, Z is NH-CH2CH2CH3 l R is -CH2- C = -CH; Compound of Formula (XI): Y is H, Z is NH-CH (CH3) 2, R is -CH2- C = CH; Compound of Formula (XI): Y is OH, Z is H, R is -CH2-C = CH; Compound of Formula (XI): Y is H, Z is OH, R is -CH2-C = CH;
Compound of Formula (IV): R is -CH2CH = CH2, Rb is H, Rc is H, Rd is
OH, Re is OCH3, Rf is hydrogen; Compound of Formula (IV): R is -CHz-C = CH, Rb is H, Rc is H, Rd is
OH, Re is OCH3, Rf is hydrogen; Compound of Formula (IV): R is -CH2-C- = N. Rb is H, Rc is H, Rd is OH,
Rβ is OCH3I Rf is hydrogen; Compound of Formula (V): R is -CH2CH = CH2, Rb is H, Rc is H, Rd is
OH, Re is OCH3, Rf is hydrogen; Compound of Formula (V): R is -CH2-C = CH, Rb is H, Rc is H, Rd is OH, Rβ is OCH3, Rf is hydrogen; Compound of Formula (V): R is -CH2-C = N, Rb is H, Rc is H, Rd is OH,
Re is OCH3, Rf is hydrogen; Compound of Formula (VI): R is -CH2CH = CH2, Ra is OH, Rb is H, Rc is
H, Rd is OH, Rβ is OCH3, Rf is hydrogen; Compound of Formula (VI): R is -CH2-C = CH, R is OH, Rb is H, Rc is
H, Rd is OH, Re is OCH3I Rf is hydrogen; Compound of Formula (VI): R is -CH2-C = N, Ra is OH, Rb is H, Rc is H,
Rd is OH, Re is OCH3l Rf is hydrogen; Compound of the Formula (VII): R is -CH2CH = CH2 and W, Rb, Rc, Rd, Re, Rf and R9 are as previously defined; Compound of the Formula (VII): R is -CH2-C = CH and W, Rb, Rc, Rd, Re, Rf and
R9 are as previously defined; Compound of the Formula (VII): R is -CH2-C = N and W, R, Rc, Rd, Re, Rf and
Rg are as previously defined; Compound of the Formula (VII I): R is -CH2-CH = CH2 and A, B, D, E, Rb, Rc, Rd, Rβ and Rf are as previously defined; Compound of Formula (VIII): R is -CH2-C = CH and A, B, D, E, Rb, Rc, Rd,
Rβ and Rf are as previously defined; Compound of Formula (VIII): R is -CH2-C = N and A, B, D, E, Rb, Rc, Rd, Re and Rf are as previously defined; Compound of the formula (IX): R is -CH2CH = CH2l and A, B, D, E, Rb, R °, Rd,
Re, Rf and Rh are as previously defined; Compound of the formula (IX): R is -CH2-C = CH, and A, B, D, E, Rb, Rc, Rd, Rβ,
Rf and Rh are as previously defined; Compound of the formula (IX): R is -CH2-C = N, and A, B, D, E, Rb, Rc, Rd, Re,
Rf and Rh are as previously defined; Compound of Formula (II): X is = O, R is -CH2CH = CH2, Rc and Rd taken together are = O, and Ra, Rb, Re and Rf are as previously defined thirst; Compound of Formula (II): X is = O, R is -CH2-C-sCH, Rc and Rd taken together are = O, and Ra, Rb, Re and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C = N, R ° and Rd taken together are = O, and Ra, Rb, Rβ and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2CH = CH2, Rc is -OH, Rd is -H, Re is -OCH3; and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C- = CH, R ° is -OH, Rd is
-H, Re is -OCH3; and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C = N, Rc is -OH, Rd is -H, Re is -.OCH3; and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2CH = CH2, Rc is -N (CH3) 2, Rd is -H, Re is -OCH3 and Ra, Rb Rf are as previously defined;
Compound of Formula (II): X is = O, R is -CH2-C = CH, Rc is -N (CH3) 2, Rd is -H, Re is -OCH3 and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C- = N, R ° is -N (CH3) 2, Rd is -H, Rβ is -OCH3 and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2CH = CH2, Rc is -H, Rd is -N (CH3) 2, Re is -OCH3 and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C = CH, Rc is -H, Rd is -N (CH3) 2, Re is -OCH3 and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C = N, R ° is -H, Rd is -N (CH3) 2, Rβ is -OCH3 and Ra, Rb, and Rf are as were previously defined; Compound of Formula (II): X is = O, R is -CH2CH = CH2, Rc is -H, Rd is -OCH3, Rc is -F and Ra, Rb and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C = CH, Rc is -H, Rd is -OCH3l Rβ is -F and Ra, R and Rf are as previously defined; and Compound of Formula (II): X is = 0, R is -CH2-C = N, Rc is -H, Rd is -OCH3, Rc is -F and Ra, Rb and Rf are as previously defined; as well as the pharmaceutically acceptable salts, esters and pro-drugs thereof. Preferred compounds are selected from the group consisting of: Compound of Formula (X) X is = N-O- (1-isopropoxycyclohexyl), R is allyl; Compound of Formula (X) X is = O, R is allyl; Compound of Formula (X) X is = O, R is propyl; Compound of Formula (X) X is = O, R is 2,3-dihydroxypropyl; Compound of Formula (X) X is = O, R is 2,3-epoxypropyl; Compound of Formula (X) X is = O, R is 2-hydroxy-3- (imidazol-1-yl) propyl; Compound of Formula (X): X is = O, R is 2-hydroxy-3- (morpholin-4H) propyl; Compound of Formula (X): X is = O, R is 2-hydroxy-3- (benzylamine) propyl; Compound of the Formula (X>: X is = O, R is 2-oxoethyl, Compound of the Formula (X, >: Xes = O, R is 2-oxopropyl; Compound of the Formula (X. |: X es = O, R is -CHz-CsCH; Compound of the Formula (X,: X is = O, R is -CH2-CHOH-CH2-N3; Compound of the Formula (X.: Xes = O, R is - CH2-CH = N-OH: Compound of the Formula (X.: X is = O, R is -CH2-CH2OH; Compound of the Formula (X->: X is = O, R is -CH2-CH2NH2; Compound of the Formula (x;: Xes = O, R is -CH2-CN; Compound of the Formula (X. >: X is = o, R is -CH2-Phenyl; Compound of the Formula (x;: X es = O, R is -CH2-CH = CH (Phenyl); Compound of the Formula (X;: X is = O, R is -CH2-CH = N-0-CH3; Compound of the Formula (x; X is = O, R is -CH2-CH = NO-CH2-Phenyl; Compound of the Formula (X;: X is = o, R is -CH2-CH = NN (CH3) 2; Compound of the Formula (X ]: X is = O, R is -CH2-CH = N-NH (CH3); Compound of the Formula (X]: X is = O, R is -CH2-CH = N- (4-Morpholinyl); of Formula (X): X is = O, R is -CH2-CH = N-NH (Feni lo);
Compound of the Formula (X;: X is = O, R is -CH2-CH = NN (Phenyl) 2, as well as the pharmaceutically acceptable salts, stteerreesses and pprro-drugs thereof The most preferred compounds are selected from the group consisting of: group consisting of: Compound of Formula (X): X is = O, R is allyl, Compound of Formula (X): X is = O, R is 2-hydroxy-3- (benzylamine) propyl; Formula (X): X is = O, R is 2-oxopropyl, Compound of Formula (X): X is = O, R is -CH2-C = CH; Compound of Formula (X): X is = O, R is -CH2-CH = N-OH: Compound of Formula (X): X is = O, R is -CH2-CH2OH; Compound of Formula (X): X is = O, R is -CH2 -CH2NH2; and Compound of the Formula (X): X is = O, R is CH2-CN, as well as the pharmaceutically acceptable salts, esters and pro-drugs thereof A process for the preparation of substituted macrolide derivatives in 6-0- that have the formulas:
(ip >
(TV);
(V);
(SAW); (GO); (Vip);
eleven
(DO;
where X is: (1) = 0 (2) = N-OH (3) = NO-R1 wherein R1 is (a) unsubstituted alkyl, (b) C1-C12 alkyl substituted with aryl, (c) substituted C 1 -C 2 alkyl with substituted aryl, (d) C 3 -C 2 cycloalkyl, (e) -Si- (R 11) (R 12) (R 13) wherein R 11, R 2 and R 13 are independently selected each from C1-C12 alkyl,
(f) -Si- (aryl) 3 > or (4) = NOC (R9) (R10) -O-R1 wherein R1 is as defined above and R9 and R10 are independently selected each from the group consisting of: (a) hydrogen, (b) C1- alkyl C12 unsubstituted, (c) dC? 2 alkyl substituted with aryl, and (d) substituted C1-C12 alkyl with substituted aryl, or R9 and R10 taken together with the carbon to which they are attached form a C3 cycloalkyl compound C? 2; Ra is hydrogen or hydroxy; Rb is hydrogen or hydroxy; one of Rc and Rd is hydrogen and the other of Rc and Rd is: (1) hydroxy, (2) protected hydroxy, (3) halogen, or (4) NR3R4 wherein R3 and R4 are independently selected from:
(a) hydrogen, (b) C 1 -C 12 alkyl, (c) C 1 -C 12 alkyl substituted with aryl, (d) C 1 -C 12 alkyl substituted with substituted aryl, or R 3 and R 4 taken together with carbon at which are linked form a 3-7 membered heterocycloalkyl ring, or Rc and Rd taken together are: (1) = 0, (2) = N-OH, (3) = N-OR1 where R1 is as defined before; Re is methoxy, fluoro or hydroxy; Rf is hydrogen or a hydroxy protecting group; R9 is selected from the group consisting of: (1) unsubstituted C? -C6 alkyl, (2) substituted C? -C6 alkyl with one or more substituents selected from the group consisting of: (a) aryl, (b) substituted aryl, (c) heteroaryl, (d) substituted heteroaryl, (e) heteroarylalkyl, (f) hydroxy, (g) C? -C6 alkoxy, (h) NR3R4 wherein R3 and R4 are as defined above, and (i) -CH2-M-Rs wherein M is selected from a group consisting of: (i) -O-, (ii) -NH-, (iii) -NMe-, (iv) -S (O) n- where n is 0, 1 or 2, (v) -NHC (= O) -, and (vi) -C (= O) -NH-, and Rs is selected from a group consisting of: (i) ) - (CH2) n-aryl wherein n is 0, 1 or 2, (ii) - (CH2) p-substituted aryl wherein n is 0, 1 or 2, (iii) - (CH2) n-heteroaryl in where n = 0, 1 or 2, (iv) - (CH2) n-substituted heteroaryl wherein n is 0, 1 or 2, and (v) - (CH2) n-heteroarylalkyl where n is 0, 1 or 2 , (3) C3-C? 2 cycloalkyl, (4) aryl, (5) substituted aryl, (6) heteroaryl, and (7) substituted heteroaryl; R is selected from the group consisting of: (1) Ci alkyl substituted with a substituent selected from the group consisting of: (a) F, (b) S (O) nR6 wherein n is 0, 1 or 2 and alkyl of C? -C3 or alkyl of
C? -C3 substituted with aryl, (c) NHC (O) R6 wherein R6 is as defined above, and (d) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (2) alkyl of C2-C10; (3) C2-C10 alkyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C? -C3 alkoxy, (d) oxo (C = O ), (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 are as previously defined, (i) = NO-R6 where R6 is as previously defined, (i) -CN, (k) S (O) "R6 where n is 0, 1 or 2 and R6 is C? -C3 alkyl or C? -C3 alkyl substituted with aryl, (I) aryl, (m) substituted aryl, (n) heteroaryl, (o) substituted heteroaryl, (p) C3-C7 cycloalkyl, ( q) (heteroaryl) alkyl, (r) NHC (O) R6 wherein R6 is as previously defined, (s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N-NR3R4 wherein R3 and R4 are as previously defined, (u) = N-NHC (O) R6 where R6 is as previously defined, and (v) = N-NHC (O) NR3R4 where R3 and R4 are as they were defined previously; (4) C 2 -C 0 alkenyl; (5) C2-C al al alkenyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C?-C3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 are as previously defined,
(i) = NO-R6 wherein R6 is as previously defined, (j) -C --- N, (k) S (O) nR6 where n is 0, 1 or 2 and R6 is alkyl of d- C3 or C?-C3 alkyl substituted with aryl, (I) aryl, (m) substituted aryl, (n) heteroaryl, (o) substituted heteroaryl, (p) C3-C7 cycloalkyl, (q) (heteroaryl) alkyl , (r) NHC (O) R6 where R6 is as previously defined,
(s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N-NR3R4 where R3 and R4 are as previously defined, (u) = N-NHC (0) R6 where R6 is as previously defined, and (v) = N-NHC (O) NR3R4 wherein R3 and R4 are as previously defined;
(6) Alkynyl of C2-C? 0; and (7) C2-C alkynyl or substituted with one or more substituents selected from the group consisting of: (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) heteroaryl replaced; one of Y and Z is hydrogen and the other is selected from a group consisting of: (1) hydrogen, (2) hydroxy, (3) protected hydroxy, and (4) NR3R4 wherein R3 and R4 are as defined above; W is: (1) -o-, (2) -NH-, (3) -NMe-, or (4) absent; A, B, D and E are, in each occurrence, independently selected from the group consisting of: (1) hydrogen, (2) unsubstituted alkyl, and (3) substituted C 1 -C 6 alkyl with one or more substituents selected from the group consisting of: (a) aryl, (b) substituted aryl, (c) heteroaryl, (d) substituted heteroaryl, (e) heteroarylalkyou, (f) hydroxy, (g) C? -C6 alkoxy, h) NR3-R4, wherein R3 and R4 are as defined above, e (i) -CH2-M-RS wherein M is selected from a group consisting of: (0 -O-, (ii) -NH -, (iii) -NMe-, (iv) -S (O) n- where n is 0, 1 or 2, (v) -NHC (= O) -, and (vi) -C (= O) -NH-, and Rs is selected from a group consisting of: (i) - (CH2) n-aryl wherein n is 0, 1 or 2, (ii) - (CH2) n-aryl substituted where n is 0, 1 or 2, (iii) - (CH2) n-heteroaryl wherein n = 0, 1 or 2, (iv) - (CH2) p-substituted heteroaryl wherein n is 0, 1 or 2, and (v) ) - (CH2) p-heteroarylalkyl wherein n is 0, 1 or 2, or any pair of substituents, consist of of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7- membered ring optionally containing a hetero function selected from: (D- o-, (2) -S (O) n-, where n is 0, 1 or 2, (3) -NH-, (4) -N (CH,) -, and (5) -N (R5 ) - where R5 is as previously defined, is a method that comprises: (a) treating a compound that has the formulas:
wherein Rp is a hydroxy protecting group and V is = NO-R1 or = NOC (R9) (R10) -O-R1 wherein R1, R9 and R10 are as defined above, with a base, such as hydroxide potassium, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potassium tert-butoxide, potassium isobutoxide, in an aprotic solvent, as defined below, which does not adversely affect the reaction, preferably dimethylsulfoxide, diethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone, with cooling or heating, depending on the conditions used, at a temperature of about -15 ° C to about 50 ° C, for a period of 0.5 hours to 10 days, preferably 1-5 days, with an alkylating agent such as or allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, a-bromo-p-tolunitrile, cinnamyl bromide, 4 methyl-bromocotonate, crotyl bromide, 1-bromo-2-pentene, 3-bromo-1-propenyl phenyl sulfone, 3-bromo-1-trimethylsilyl-1-propynyl, 3-bromo-2-octyne, -bromo-2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromomethyl quinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2- bromoacetophenone, 1-bromo-2-butanone, bromochloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-1-propene, allyl-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate, or n-butyl-O- methanesulfonate; to give a compound that has the formula:
where A, B, D, E, W, X, Y, Z, Ra, Rb, Rc, Rd, Re, Rf, R9, and Rh are as defined above, V is = NO-R1 or = NOC ( R9) (R10) -O-R1 wherein R1, R9 and R10 are as defined above, and R is the "alkyl group" derived from the corresponding alkylating agent; (b) deprotecting the hydroxyl groups in 2'- and 4'-, for example, using acetic acid in water and acetonitrile to give a compound of the formula:
15
wherein A, B, D, E, W, X, Y, Z, Ra, Rb, Rc, Rd, Re, Rf, R9 and Rh are as defined above and R is the "alkyl group" derived from the alkylating agent correspondent; and (c) deoximation, for example, using inorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, dithionate of sodium, potassium thiosulfate, or potassium metabisulfite, in a solvent such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol, or a mixture of one or more of the mentioned solvents to give the desired products. A preferred process for the preparation of 6-O- substituted macrolide compounds having the formula:
of X is: (1) = O, (2) = N-OH, (3) = NO-R1 wherein R1 is: (a) unsubstituted C? -C? 2 alkyl, (b) C-alkyl ? -C-? 2 substituted with aryl, (c) substituted C? -C? 2 alkyl with substituted aryl, (d) C3-C12 cycloalkyl, (e) -Si- (R1 1) (R12) (R13) ) wherein R11, R12 and R13 are each independently selected from d-Ci? alkyl, (f) -Si- (aryl) 3l or (4) = NOC (R9) (R10) -O-R1 in where R1 is as defined above and R9 and R10 are each independently selected from the group consisting of: (a) hydrogen, (b) unsubstituted C? -C? 2 alkyl, (c) C? -C alkyl 2 substituted with aryl, (d) substituted C 1 -C 2 alkyl with substituted aryl, or R 9 and R 10 taken together with the carbon to which they are attached form a cycloalkyl ring of C 3 -C 2; R is selected from the group consisting of: (1) Ci alkyl substituted with a substituent selected from the group consisting of: (a) F, (b) S (O) pR6 wherein n is 0, 1 or 2 and R6 is d-C3 alkyl or C?-C3 alkyl substituted with aryl, (c) NHC (O) R6 wherein R6 is as defined above, and (d) NHC (O) NR3R4 wherein R3 and R4 are selected independently of hydrogen and C 1 -C 3 alkyl, (2) C 2 -C 10 alkyl; (3) C 2 -C 0 alkyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C 1 -C 3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 are as previously defined, (i) = NO-R6 where R6 is as previously defined, G) -C = N, (k) S (O) "R6 where n is 0, 1 or 2 and R6 is C?-C3 alkyl or d-C3 alkyl substituted with aryl, (I) aryl, (m) substituted aryl, (n) heteroaryl, (o) substituted heteroaryl, (p) C3-C7 cycloalkyl, (q) (heteroaryl) alkyl, (r) NHC (O) R6 wherein R6 is as previously defined,
(s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N-NR3R4 where R3 and R4 are as previously defined, (u) = N-NHC (O) R6 where R6 is as previously defined, and (v) = N-NHC (O) NR3R4 wherein R3 and R4 are as previously defined; (4) C2-C? Alkenyl. (5) C2-C al al alkenyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C?-C3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 are as previously defined,
(i) = NO-R6 where R6 is as previously defined, (j) -dN, (k) S (O) "R6 where n is 0, 1 or 2 and R6 is C? -C3 alkyl or C3-substituted alkyl with aryl, (I) aryl, (m) substituted aryl, (n) heteroaryl, (o) susbtituido heteroaryl, (p) C3-C7 cycloalkyl, (q) (heteroaryl) alkyl, (r) ) NHC (O) R6 where R6 is as previously defined,
(s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N-NR3R4 where R3 and R4 are as previously defined, (u) = N-NHC (O) R6 where R6 is as previously defined, and (v) = N-NHC (O) NR3R4 wherein R3 and R4 are as previously defined; (6) C2-C10 alkynyl; and (7) C2-C10 alkynyl substituted with one or more substituents selected from the group consisting of: (a) trialkylisilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) substituted heteroaryl; it is a method that comprises: (a) treating a compound that has the formulas:
wherein R p is a hydroxy protecting group and V is = NO-R 1 or = N-0-C (R 9) (R 10) -O-R 1 wherein R 1, R 9 and R 10 are as defined above, with a base, such as potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potassium tert-butoxide, potassium isobutoxide, in an aprotic solvent, as defined below, which does not adversely affects the reaction, preferably dimethyl sulfoxide, diethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone, with cooling or heating, depending on the conditions used, at a temperature of about -15 ° C to about 50 ° C, for a period of 0.5 hours to 10 days, preferably 1-5 days, with an alkylating agent such such as allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, α-bromo-p-tolunitrile, cinnamyl bromide, 4 -methyl bromocrotonate, crotyl bromide, 1-bromo-2-pentene, 3-bromo-1 -propenyl phenyl sulfone, 3-bromo-1-trimethylsilyl-1-propino, 3-bromo-2-octino, 1 -bromo -2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromomethyl quinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bromochloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-1-propene, allyl-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate, or n-butyl-O-methanesulfonate; to give a compound that has the formula:
wherein V and Rp are as defined above and R is the "alkyl group" derived from the corresponding alkylating agent; (b) deprotecting the hydroxyl groups in 2'- and 4'-, for example, using acetic acid in water and acetonitrile to give a compound having the formula:
(c) deoximation, for example, using inorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate , potassium thiosulfate, or potassium metabisulfite in a solvent such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol, or a mixture of one or more of the aforementioned solvents. A more preferred process for the preparation of 6-O- substituted macrolide compounds having the formula:
wherein X is: (1) = O, (2) = N-OH, (3) = NO-R1 wherein R1 is (a) unsubstituted C? -C? 2 alkyl, (b) C1 alkyl -C12 substituted with aryl, (c) substituted C? -C? 2 alkyl with substituted aryl, (d) C3-C7 cycloalkyl, (e) -Si- (R11) (R12) (R13) wherein R11, R12 and R13 are each independently selected from dC? 2 alkyls, (f) -Si- (aryl) 3, or (4) = NOC (R9) (R10) -O-R1 wherein R1 is as defined above and R9 and R10 are each independently selected from the group consisting of: (a) hydrogen, (b) unsubstituted C? -C? 2 alkyl, (c) C? -C? 2 alkyl substituted with aryl, and (d) dC? 2 alkyl substituted with substituted aryl, or R9 and R10 taken together with the carbon to which they are attached form a cycloalkyl ring of C3-C?; and R is selected from the group consisting of: (1) d-alkyl substituted with a substituent selected from the group consisting of: (a) F. (b) S (O) "R6 wherein n is 0, 1 or 2 and C?-C3 alkyl or aryl-substituted d-C3 alkyl, (c) NHC (0) R6 wherein R6 is as defined above, and (d) NHC (O) NR3R4 wherein R3 and R4 are selected independently of hydrogen and C 1 -C 3 alkyl, (2) C 2 -C 0 alkyl 0; (3) C 2 -C 0 alkyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C 1 -C 3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 are as previously defined, (i) = NO-R6 where R6 is as previously defined, (j) -C - .N, (k) S (O) nR6 where n is 0, 1 or 2 and R6 is C? -C3 alkyl or C? -C3 alkyl substituted with aryl, (I) aryl, (m) substituted aryl, (n) heteroaryl, (o) substituted heteroaryl, (p) C3 cycloalkyl -C7, (q) (heteroaryl) alkyl, (r) NHC (O) R6 wherein R6 is as previously defined, (s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N-NR3R4 where R3 and R4 are as previously defined, (u) = N-NHC (O) R6 where R6 is as previously defined, and (v) = N-NHC (O) NR3R4 where R3 and R4 are as defined prev iamente;
(4) C2-C alkenyl; (5) C 2 -C 0 alkenyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) d-C 3 alkoxy, (d) oxo (C = O ), (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 are as previously defined, (i) = NO-R6 where R6 is as previously defined, (j) -C- = N, (k) S (O) "R6 where n is 0, 1 or 2 and R6 is d-C3 alkyl or C?-C3 alkyl substituted with aryl, (I) aryl, (m) substituted aryl, (n) heteroaryl, (o) heterobaryl substituted, (p) cycloalkyl of dd, ( q) (heteroaryl) alkyl, (r) NHC (O) R6 wherein R6 is as previously defined, (s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N -NR3R4 wherein R3 and R4 are as previously defined, (u) = N-NHC (O) R6 where R6 is as previously defined, and (v) = N-NHC (O) NR3R4 where R3 and R4 they are as defined on previously; (6) Alkynyl of C2-d0; and (7) C2-C alkynyl or substituted with one or more substituents selected from the group consisting of: (a) trialkylsily, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) heteroaryl replaced; method comprising: (a) treating a compound having the formula:
wherein R p is trimethylsilyl and V is O- (l-isopropoxycyclohexyl) oxime with potassium hydroxide in a mixture of THF and DMSO with an alkylating agent such as allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide , 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, a-bromo-p-tolunitrile, cinnamyl bromide, methyl 4-bromocronate, crotyl bromide, 1-bromo-2-pentene, 3 -bromo-1-propenyl phenyl sulfone, 3-bromo-1-trimethylsilyl-1-propynyl, 3-bromo-2-octyne, 1-bromo-2-butyne, 2-picolyl chloride, 3-picolyl chloride, chloride of 4-picolyl, 4-bromomethyl quinoline, bromoacetonitrile, epichlorhydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bromochloromethane, bromomethyl phenyl sulfone, 1, 3 -dibromo-1 -propanol, allyl O-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate, or n-butyl-O-methanesulfonate; to give a compound that has the formula:
wherein V and Rp are as defined above and R is the "alkyl group" derived from the corresponding alkylating agent;
(b) deprotecting the hydroxyl groups in 2'- and 4'- using acetic acid in water and acetonitrile to give a compound having the formula:
; and (c) deoximating the 9-oxime using NaHSO3 and formic acid in ethanol-water to give the desired product. DEFINITIONS The term "C 1 -d 2 alkyl" as used herein refers to saturated straight or branched chain hydrocarbon radicals containing between 1 and 12 carbon atoms. Examples of C1-C3 alkyl radicals include methyl, ethyl, propyl and isopropyl, and examples of C1-C6 alkyl radicals, but are not limited to, methyl, ethyl, propyl, isopropyl, N-butyl, tert-butyl, neopentyl and N-hexyl. The term "C6-C6 alkoxy" as used herein refers to a C6-C6 alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of alcohol
C? -C6, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, N-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
The term "alkenyl" as used herein refers to a branched or straight hydrocarbon chain comprising from 2 to 10 carbon atoms also comprising one or more carbon-carbon double bonds. Representative alkenyl groups include 2-propenyl (ie, allyl), 3-methyl-2-butenyl, 3,7-dimethyl-2] 6-octadienyl, 4,8-dimethyl-3,7-nonadienyl, 3.7, 11-trimethyl-2,6,10-dodecatrinyl and the like. The term "alkenyl" as used herein refers to a branched or straight hydrocarbon chain comprising from 2 to 10 carbon atoms also comprising one or more triple carbon-carbon bonds. Representative alkenyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl and the like. The term "C 1 -C 3 alkyl amino" as used herein refers to one or two C? -C 3 alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom . Examples of C 1 -C 3 -alkylamino include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, and propylamino. The term "aprotic solvent" as used herein refers to a solvent that is relatively inert to proton activity, that is, it does not act as a proton donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heteroaryl compounds, such as, example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, dis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or their mixtures may be preferred for specific compounds and reaction conditions, depending on such factors as the solubility of reagents, the reactivity of reagents and preferred temperature ranges, for example. Additional discussions of aprotic solvents can be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification. Fourth Edition, edited by John Riddick, et al; Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings including but not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the similar ones. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy , alkoxy carbonyl and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl. The term "C3-C12 cycloalkyl" as used herein refers to carbocyclic groups of three to twelve carbons, respectively, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "C3-C3 cycloalkyl C3-C3 alkyl", as used herein, refers to a C3-C5 alkyl cyclo radical, as defined above, linked to an alkyl radical of C3-C3. by replacing a hydrogen atom of the latter. The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine. The term "heteroaryl", as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; 0, 1 or 2 ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbons, the radical being attached to the rest of the molecule via any of the ring atoms, such as, for example, pyridinyl, pyrazinyl, pyrinidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, izoquinolinyl, and the like. The term "heteroarylalkyl" as used herein, refers to a non-aromatic 5-, 6- or 7- membered ring or a bi- or tricyclic group comprising rings of 6 fused members having between 1 and 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, where (i) each five-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally being oxidized (iii) the nitrogen heteroatom may optionally be quaternized and (iv) any of the above heteroaryl rings may be fused to a benzene ring. Representative heterocycles, include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolinidyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. "Hydroxy protecting group", as used herein, refers to an easily removable group which is known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy protecting groups is well known in the art to protect groups against undesirable reactions during a synthesis process and many such protective groups are known, cf., for example, T. H. Greene v. G. M. Wuts. Protective Groups in Inorganic Svnthesis. Second Edition John Wiley & Sons, N.Y. (1991). Examples of hydroxide protecting groups include, but are not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, acyl substituted with an aromatic group, and the like. The term "ketone protecting group", as used herein, refers to an easily removable group which is known in the art to protect a ketone group against undesirable reactions during synthesis procedures and to be selectively removable. The use of ketone protecting groups is well known in the art to protect groups against undesirable reactions during a synthesis process and many such protective groups are known, cf., for example, T.H. Greene and P.G.M. Wuts, Protective Groups in Inorganic Synthesis, Second Edition, John Wiley & amp;; Sons, NY (1991). Examples of ketone protecting groups include but are not limited to ketals, oximes, O-substituted oximes for example O-benzyl oxime, O-phenylthiomethyl oxime, 1-isopropoxycyclohexyl oxime, and the like.
The term "protected hydroxy" refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example. The term "protogenic organic solvent" as used herein refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or their mixtures may be preferred for specific compounds and reaction conditions, depending on such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Additional discussions of protivogenic solvents can be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Phvsical Properties and Methods of Purification. Fourth Edition, edited by John A. Riddick, et al; vol. II, in the Technigues of Chemistry Series, John Wilie & Sons, NY (1986). The term "substituted aryl" as used herein refers to an aryl group as defined herein substituted by the independent substitution of 1, 2 or 3 of the hydrogen atoms therein with Cl, Br, F, I, OH, C? -C3 alkyl, C? -C6 alkoxy, methoxymethoxy, amino, or C1-C3 alkyl amino. The term "substituted heteroaryl" as used herein refers to a heteroaryl group as defined herein substituted by a substituent independent of one, two or three of the hydrogen atoms therein with Cl, Br, F, I , OH C 1 -C 3 alkyl C 1 -C 6 alkoxy, methoxymethoxy, amino, or alkylamino of dC 3. The term "substituted heterocycloalkyl" as used herein, refers to a heterocycloalkyl group, as defined above, substituted by independent substitution of one, two or three hydrogen atoms therein with Cl, Br, F, I, OH C? -C3 alkyl) C? C6 alkoxy, methoxymethoxy, amino, or C? -C3 alkyl amino. There may be numerous asymmetric centers in the compounds of the present invention. Except where noted otherwise, the present invention contemplates the various stereoisomers and mixtures thereof. Consequently, wherever a ligature is represented by a wavy line, it is intended that a mixture of stereo orientations or an individual isomer of assigned or unassigned orientation may be present. As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of the medical screening judgment, suitable for use in contact with the tissues of human and lower animals without toxicity and irritation response or undue allergic and the like, and are measured with a reasonable risk / benefit ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge, et al .: describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the isolation and final purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid , maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camforate, camphorsulfonate, citrate, cyclopentanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroxyor 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurisulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali metal or alkaline earth salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counteracting agents such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that are easily broken in the human body to leave the parent compound or one of its salts. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkane, and alkanedioic acids, in which each alkyl or alkenyl portion advantageously has no more than 6 carbon atoms. Examples of particular esters include formats, acetates, propionates, butyrates, acriiates and ethyl succinates. The term "pharmaceutically acceptable pro-drugs" as used herein refers to those pro-drugs of the compounds of the present invention which are, within the scope of the medical sounding judgment, suitable for use in contact with the tissues of humans and lower animals with an irritant and allergic allergic response and the like, measured with a reasonable risk / benefit ratio, and effective for their intended use, as well as the zitherine forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to give the parent compound of the above formula, for example by hydrolysis in blood. A deep discussion provides T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems. Vol. 14 of the A. C.S. Symposium Series, and Edward B. Roche ed; Bioreversible Carriers in Drug Design. American Pharmaceutical Association and Pergamon Press, 1987, both are incorporated herein by reference. The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers As used herein, the term "pharmaceutically acceptable carrier" means an encapsulating, diluting material. , inert solid, semi-solid or liquid, non-toxic, or auxiliary formulation of any kind Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and starch potato, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, powdered tragacanth, malt, gelatin, talcum, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, seed oil of cotton, safflower oil, sesame oil, olive oil, ceite of corn and soybean oil; glycols; such as propylene glycol, esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate as well as coloring agents, release agents, coating agents, sweeteners, flavoring and flavoring agents, preservatives and antioxidants as well they may be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, infracysternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), orally, or as an oral or nasal spray. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate. , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor bean, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids, and their mixtures. In addition to the inert diluents, the oral compositions may also include auxiliaries such as wetting agents, emulsifying and suspending agents, sweeteners, flavors and flavoring agents. Injectable preparations, for example injectable sterile aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a non-toxic diluent or solvent acceptable parenterally, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, isotonic sodium chloride solution and U.S.P. In addition, sterile, sterile oils are conventionally employed as a solvent or suspension medium. For this purpose any fixed oil of easy digestion can be used including mono or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use. In order to prolong the effect of a drug, it is often desirable to decrease the absorption rate of the drug from subcutaneous or intramuscular injections. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The speed of absorption of the drug then depends on its rate of dissolution which, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, the delayed absorption of a drug form administered parenterally is achieved by dissolving or suspending the drug in an oil vehicle. Injectable storage forms are made by forming micro-encapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug to polymer ratio and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (portoesters) and poly (anhydrides). Injectable depot formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at room temperature. of body and therefore melt in the rectum or vaginal cavity and release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or dicalcium phosphate and / or carriers or extenders such as starches, lactose, sucrose, glucose, mannitol and salicylic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato starch or tapioca, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and monostearate of glycerol, h) absorbents such as kaolin and bentonite clay, i) lubricants such as talc, calcium stearate, magnesium stearate, glyco of solid polyethylene, sodium laurisulfate, and their mixtures. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type can also be employed as fillers in gelatin capsules with hard fillers using such excipients as lactose sugar or milk as well as polyethylene glycols of high molecular weight and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and coatings such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain agents or pacifiers and may also be of a composition that they release the active ingredients only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedded compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be employed as fillers in gelatin capsules with soft and hard fillers using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The active compounds may also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as empiric coatings, release controlling coatings and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances in addition to inert diluents, e.g., foil lubricants and other sheeting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain agents or pacifiers and may also be of a composition that they release the active ingredient only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedded compositions that can be used include polymeric substances and waxes. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as fats, animal and vegetable oils, waxes, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, ventonites, salicylic acid, talc and zinc oxide, or their mixtures.
Powders and sprays may contain, in addition to the compounds of this invention, excipients such as lactose, talc, salicylic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants such as chlorofluorohydrocarbons. Transdermal patches have the additional advantage of providing a controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or supplying the compound in the appropriate medium. The absorption enhancers can also be used to increase the flow of the compound through the skin. The speed can be controlled either by providing a speed control membrane or by dispersing the compound in a polymer matrix or gel. In accordance with the methods of treatment of the present invention, bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and such time as is necessary to achieve the desired result. By a "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit-risk ratio applicable to any medical treatment. It will be understood, however, that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of the medical judgment of abscultation. The therapeutically effective specific dose for any particular patient will depend on a variety of factors including the condition to be treated and the severity of the condition; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the administration time, the route of administration, and the speed and secretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound used; and similar factors well known in the medical arts. The total daily dosage of the compounds of this invention administered to a human or other mammal in single or divided doses may be in amounts, for example, from 0.01 to 50 mg / kg body weight or more usually from 0.1 to 25 mg / kg of body weight. The single dose compositions may contain such amounts or submultiples thereof to prepare the daily dose. In general, treatment regimens in accordance with the present invention comprise administering to a patient in need of such treatment from about 10 mg to about 1000 mg of the compounds of this invention per day in single or multiple doses.
ABBREVIATIONS The abbreviations that have been used in the descriptions of the scheme and the examples that follow are: AIBN for asodisisobutyrythritil; Bu3SNH for tributyltin hydride, CDI for carbonyldiimidazole; DBU for 1,8-diazabicyclo (5.4.0) undec-7-nene; DEAD for diethylazodicarboxylate; DMF for dimethylformamide; DMSO for dimethylsulfoxide; DPPA for diphenylphosphorylazide; Et 3 N for triethylamine; EtOAc for ethyl acetate; ET2O for diethyl ethyl; EtOH for ethanol; HOAc for acetic acid; MeOH for methanol; NaN (TMS) 2 for sodium (bistrimethylsilyl) amide; NMMO for N-methylformolin N-oxide; TEA for triethylamine; THF for tetrahydrofuran; and TPP for triphenylphosphine.
METHODS OF SYNTHESIS The compounds and processes of the present invention will be better understood collectively with the following synthesis schemes that illustrate the methods by which the compounds of the invention can be prepared. Groups A, B, D, E, W, X, Y, Z, Ra, Rb, Rc, Rd, Re, Rf, Rg, and Rh are as defined above unless otherwise specified below. Scheme I illustrates the preparation of the starting material derived from erythromycin A, a compound of formula (XII). The preparation of protected erythromycin A is described in the following U.S. Patents, US 4,990,602; US 4,331, 803; US 4,680,368; and US 4,670,549 which are incorporated by reference. Also incorporated by reference is European Patent Application EP 260,938. In general, the ketone-9 of compound 1 is protected, for example as an oxime (V is = NO-OR1 or = NOC (R9) (R10) -O-R1 wherein R1, R9 and R10 are as defined above ), and then either as a separate step or in the same vessel, the hydroxyl at 2'-and 4"- are protected.The ketone-9 of the compound (1) is protected to give the compound (2) wherein V is = NO-R1 wherein R1 is as defined above or = NO-C (R9) (R10) -O-R1 wherein R1, R9 and R10 are as defined above In a preferred embodiment of the process, V is O- (1-isopropoxycyclohexyl) oxime The 2 'and 4"hydroxy groups of erythromycin A (2) are protected by reaction with a suitable hydroxy protecting reagent, such as those described by TW Greene and P.G. M. Wuts in Protective Groups in Organic Synthesis, second edition, John Wiley & Son, Inc. 1991, which is incorporated by reference, for example, acetic anhydride, benzoic anhydride, benzyl chloroformate or a trialkylsilyl chloride in an aprotic solvent. Examples of aprotic solvents are dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methylpyrrolidinone, dimethyl sulfoxide, diethylsulfoxide, NN-dimethylformamide, NN-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like. The aprotic solvents do not adversely affect the reaction, and are preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methylpyrrolidinone or a mixture thereof. The protection of hydroxy groups 2'- and 2"- of erythromycin A thus provides the compound (3) wherein Rp is a protecting group of the hydroxy In a preferred embodiment of the process, Rp is trimethylsilyl. Scheme II illustrates the general preparation of the compounds of the invention derived from erythromycin A. The alkylation of the 6-hydroxy group of compound 3 can be carried out with an alkylating agent with a solvent in the base presence at a temperature of about -15 ° C to about 50 ° C to give compound 4. Alkylating agents include chlorides, bromides, alkyl iodides or alkyl sulfonates Specific examples of alkylating agents include halide bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, bromide 4 -nitrobenzyl, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, a-bromo-p-tolunitrile, cinnamyl bromide, methyl 4-bromocrotonate, crotyl bromide, 1-bromo-2-pentene, 3-bromine 1-1 propenilsulf ona, 3-bromo-1-trimethylsilyl-1-propynyl, 3-bromo-2-octyne, 1-bromo-2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4- bromomethylquinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bromochloromethane, bromomethylphenylsulfone, 1,3-dibromo-1-propene, and the like. Examples of alkylsulfonates are: Halt O-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate, n-butyl-O-methanesulfonate and the like. It is sufficient to use one to four equivalent mole of alkylating agents relative to compound 3. Examples of the solvents used are aprotic solvents such as dimethylsulfoxide, diethylsulfoxide, NN-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like. Examples of the base that can be used include potassium hydroxide, cesium hydroxide, tetralkylammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potassium tert-butoxide, potassium isobutoxide and the like the amount of base used it is usually from 1 to 4 equivalents with respect to compound 3. The deprotection of the hydroxyl groups in 2 'and 4'- is carried out according to methods described in the literature, for example, by TW Greene and P.G.M. Wuts in Protective Groups Inorganic Svnthesis. second edition, John Wiley &; Son, Inc., 1991, which is incorporated herein by reference. The conditions used for the deprotection of the hydroxyl groups in 2'- and 4'- usually results in the conversion of X a = N-OH. (For example, using acetic acid in acetonitrile and water results in the deprotection of the hydroxyl groups in 2'- and 4'- and the conversion of X of = NO-OR1 or = ROC (R9) (R10) -O-R1 wherein R \ R9 and R10 are as defined above a = N-OH). If this is not the case, the conversion is carried out in a separate step. The deoximation reaction can be carried out according to the methods described in the literature, for example by Greene OP. CIT. and others. Examples of the deoximation agent are inorganic sulfur oxide compounds such as sodium hydrogen sulphate, sodium pyrosulfate sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate. , potassium metabisulfite and the like. Examples of the solvents used are protic solvents such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol, or a mixture of one or more of the mentioned solvents and the like. The deoximation reaction is most conveniently carried out in the presence of an organic acid such as formic acid, acetic acid and trifluoroacetic acid. The amount of acid used is from about 1 to about 10 equivalents of the amount of compound 5 used. In a preferred embodiment the deoximation is carried out using an organic acid such as formic acid in ethanol and water to give the desired product (VI.). The desired "alkylated" compound in 6-O- can be prepared directly as described above or obtained by chemical modification of a compound initially prepared "alkylated" in 6-O-. Representative examples of further elaboration of the 6- position are shown in Scheme III. For example, compound 6 wherein R is 6-O-CH2 CH = CH2 and M represents the macrolide ring system that can be further derivatized. The double ligation of the allyl compound can be (a) reduced to give the compound 6-O-propyl (7), (b) treated with osmium tetroxide to give the 2,3-dihydroxypropyl compound (8), (c) oxidized with m-chloroperoxybenzoic acid to give the epoxymethyl compound (9), (d) oxidized under Wacker conditions to give the compound 6-O-CH- (O) -CH 3 (1 1); (e) the epoxy compound can be opened with nucleophilic compounds, for example, amines or compounds containing N-heteroaryl, to give compounds containing N-side chains (1_0), and (f) the 2,3-dihydroxypropyl compound it can be oxidized with sodium periodate to give the compound 6-O-CH2-CHO (12). It is understood that the foregoing chemistry is merely illustrative and should not be taken as a limitation on the scope of the invention. Various changes and modifications to the described modalities will be apparent to those experts in the art, and can be done without departing from the spirit and scope of the same.
Although the foregoing chemistry is directed to the preparation of compounds of the formula II, the analogous compounds of the formulas III, IV, V, VI, VII, VIII and IX can be prepared in a similar manner. Compounds of the formula III wherein R is hydrogen are described in U.S. Patents US 5,075,289 and US 5,217,960 which are incorporated herein by reference. The chemistry relative to these macrolides is also described by Kirst, et al; in J. Med. Chem. 33: 3086 (1990) which is also incorporated herein by reference. Compounds of formula IV wherein R is hydrogen are described by Hunt, et al; in J. Antibiotics, 41: 1644 (1989), which is incorporated herein by reference. Compounds of formulas V, VI and VII wherein R is hydrogen are described by Baker, et al; in J. Org. Chem; 53: 2340 (1988), which is incorporated herein by reference. Compounds of the formulas VIII and IX wherein R is hydrogen are described in European Patent Application EP 559,896, which is incorporated herein by reference.
SCHEME I
SCHEME
SCHEME
-12 J2
M 'AND R "
&
\
M -
fi 11
The compounds and processes of the present invention will be better understood in relation to the following examples, which are intended as an illustration and not a limitation of the scope of the invention.
EXAMPLE 1 COMPOSED OF FORMULA (X): X is = O, R IS ALYLO. EXAMPLE 1 A COMPOUND OF FORMULA (XII): X is = N-O- (1 ISOPROPOXICICLOHEXYL), R IS ALYLO, Rp IS TRIMETILSILIL. To a solution at 0 ° C of 5 grams of the compound of formula XII wherein X is = N-O- (l-isopropoxycyclohexyl) and Rp is trimethylsilyl in 15 mL of
DMSO and 20 mL of THF were added 1.23 mL of freshly distilled allyl bromide. After about 10 minutes, a solution prepared by heating and stirring 556 mg, (2.05 equivalents) of
KOH sprayed in 25 mL of 1: 1 THF-TMSO at 50 ° C for 20-30 minutes were added as a drip for 5 minutes. After about 1 hour, the cooled reaction mixture was treated with
200 mL of EtOAc followed by 762 μL of allyl amine followed by 60 mL of water. The organic layer was washed with water followed by brine, dried over MgSO 4, filtered and concentrated in vacuo to provide 5.3 g of crude reference compound. Purification by silica gel chromatography eluted with 5% acetone in hexanes containing 0.25% triethylamine gave 2.35g (45%) of the reference compound.
EXAMPLE 1 B COMPOSED OF FORMULA (X): X ES = N-OH, R IS HALILO. To a solution of the resultant compound of Example 1A (1.7 g) in 17 mL of acetonitrile and 8.5 mL of water were added 9 mL of HOAc at room temperature. After several hours at room temperature, the reaction mixture was diluted with 200 mL of toluene and concentrated in vacuo. The obtained residue was found to contain unreacted starting material, so additional acetonitrile (15 mL), water (70 mL) and HOAc (2 mL) were added. After 2 hours, one mL of additional HOAc aliquot was added. After about 3 more hours, the reaction mixture was placed in the freezer overnight. The reaction mixture was allowed to cool to room temperature, diluted with 200 mL of toluene and concentrated in vacuo. The residue was dissolved twice with toluene and dried at constant weight (1.524 g).
EXAMPLE 1 C COMPOSED OF FORMULA (X): X ES = O, R, IS ALYLO. The resulting compound of Example 1 B (1.225 g) in 16 mL of 1: 1 EtOH-water was treated with NaHSO 3 (700 mg) and formic acid (141 μL) and heated at 86 ° C for 2.5 hours. After about three hours, the reaction mixture was allowed to cool to room temperature, diluted with 5-6 mL of water, basified with 1 N NaOH to pH 9-10 and extracted with EtOAc. The combined organic extracts were washed with brine (2x), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography eluted with 1% MeOH in methylene chloride containing 1% ammonium hydroxide to give 686 mg (57%) of the reference compound. C13 NMR (CDCI3) d 219.3 (C-9), 174.8 (C-1), 135.5 (C-17), 116.3 (C-18), 101.9 (C-1 '), 95.9 (C-1"), 79.7 (C-5), 78.8 (C-6) ), 78.5 (C-3), 74.1 (C-12), 72.4 (C-3"), 70.6 (C-1 1), 68.1 (C-5 '), 65.5 (C-16), 65.1 (C) -2 '), 49.0 (C-3"O-CH3), 45.0 (C-2), 44.1 (C-8), 39.7 (Nme2), 37.9 (C-4), 37.1 (C-10), 34.6 (C-2"), 28.4 (C-4 '), 21.00, 20.6 (C-3" CH3, C-6' CH3), 28.4 (C-4 '), 21.00, 20.6 (C-3" CH3 C-6 'CH3), 20.8 (C-14), 18.3 (C-6"), 18.1 (C-8 CH3), 15.7, 15.6 (C-2 CH3, C-6 CH3), 11.9 (C- CH 3), 10.1 (C-15), 8.9 (C-4 CH 3), MS (FAB) + m / e 774 (M + H) +, 812 (M + K) +.
EXAMPLE 2 COMPOSITE FORMULA (X): X ES = O, R IS PROPYL The resulting compound of Example 1 (100 mg) was catalytically hydrogenated in MeOH (10 mL) using a palladium on carbon catalyst and hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The crude product (93 mg) was purified by column chromatography on silica gel eluted with 1% MeOH in methylene chloride containing 1% ammonium hydroxide to give 38 mg (38%) of the reference compound. C13 NMR (CDCl 3) d 220.5 (C-9), 175.1
(C-1), 102.2 (C-1 '), 96.4 (C-1"), 79.8 (C-5), 79.0 (C-3), 78.7 (C-6), 77.8 (C-4") , 77.2, 77.0, 76.7, 76.4 (C-13), 74.4 (C-12), 72.8 (C-3"), 71 .1 (C-1 1),
68. 8, 68.5, 49.4 (C-3"-Ome), 45.3 (C-2), 44.5, 40.2 (-NMe2), 38.4 (C-7),
38. 2 (C-4), 37.4 (C-10), 35.1, 28.6, 21.8 (C-17), 21.5 (C-14), 21.3, 21.0 (C-3"Me, 6Me) , 18.7, 18.6 (C-6"Me, 8 Me), (16.2), 16.1 (C-2 Me, 6 Me)), 12.3 (C-10 Me), 10.5 (C-15), 10.1 (C-) 18), 9.4 (C-4 Me). MS (DCI / NH3) m / z 776 (M + H) +.
EXAMPLE 3 COMPOSITE FORMULA (X): X ES = O, R ES 2,3-DIHYDROXYPROPYL.
To a solution at room temperature of the resultant compound of Example 1 (100 mg) in 6 mL of THF were added (98 mg) of N-methylmorpholine N-oxide followed by 32 μL, of 4% by weight osmium tetroxide in Water. The reaction mixture was stirred overnight and then quenched by the addition of three equivalents of NaHSO 3. After stirring at room temperature for 10 minutes, the reaction mixture was filtered through a plug of silica gel eluted with 5% MeOH in methylene chloride containing 1% ammonium hydroxide to give, after concentration under reduced pressure. , the reference compound (81 mg, 77%). C13 NMR (CDCl 3) d 222.6, 221.6 (C-9), 176.9, 176.0 (C-1), 102.2 (C-1 '), 102.1, 96.5 (C-1"), 96.4, 80.0, 79.9, 79.8, 78.8, 78.7, 77.6, 77.5, 77.2, 77.0, 76.7, 74.8, 74.7 (C-12), 72.8 (C-3"), 72.8, 71 .0, 71 .0, 70.9 (C-1 1), 70.9 , 68.9, 68.5, 66.5, 66.3, 66.2, 65.8, 65.6, 63.3, 63.0 (C-1 8), 55.3, 49.3 (-OCH3), 46.3, 45.6, 45.4 (C-2), 44.7 (C-8) , 40.2 (-NMe2), 38.4, 38.2, 38.2, 37.9, 37.6, 35.1 (C-2"), 35.0, 30.8, 28.5, 28.5 (C-4 '), 21 .7, 21.5, 21.5, 21 .4, 21.0, 20.9, 18.8, 18.6, 18.5, 16.2, 16.2, 16.0, 1 1 .9 (C-10CH3), 10.4 (C-15), 10.4, 9.4 (C-4 CH3), 9.3 MS / z 808 (M + H) +.
EXAMPLE 4 COMPOSITE FORMULA (X): X ES = O, R ES 2,3-EPOXYPROPYL To a solution at room temperature of the compound resulting from Example 1 (100 mg) in 1.5 mL of methylene chloride was added ~ 170 mg of m-chloroperoxybenzoic acid. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The obtained residue was taken up in EtOAc and washed with saturated sodium bicarbonate solution (2x) followed by brine, dried over MgSO4 and concentrated in vacuo to give 93 mg of crude product. The crude product was re-dissolved in EtOAc and washed with 1 M NaHSO 3, followed by NaHSO 3 solution and brine, dried over MgSO and concentrated in vacuo. The obtained residue was chromatographed on silica gel eluted with 5% MeOH in methylene chloride containing 1% NHOH to give the reference compound. C13 NMR (CDCl 3) d 219.8, 219.0 (C-9), 175.5, 175.2 (C-1), 102.2, 102.2 (C-1 '), 96.3, 96.2 (C-1"), (80.2.79.9, 79.6 , 79.0, 78.8, 77.8, 77.7, 77.2, 77.0, 76.7, 76.6 (C-6, 5, 3, 4", 13)), 74.6 (C-12), 72.7 (C-3"), 71 .0 (C-1 1), 68.8, 68.8 (C-17), 68.5 (C-5 '), (66.2, 66.1 (C-16)), (66.0, 65.6 (C-5", 3')), 50.3, 49.8, 49.3 (3"OMe), (46.6, 45.5 (C-18)), (45.3, 45.2 (C-2)), 44.6, 44.6 (C-8), 40.2 (-NMe2), 38.4 ( C-7), 38.2, 38.2 (C-37.6, 37.5 (C-10)), 35.1 (C-2"), 35.0, 28.8 (C-4 '), (21.4, 21.2, 21.1, 20.9 (C-3"Me 6 'Me, C-14)), (18.7, 18.6, 18.5 (C-6" Me, 8 Me)), 16.1, 16.0, 15.9 (C-2Me, 6Me)), 12.2 (C-10 Me), 12.2, 10.5 (C-15), 9.3 (C-4 Me), 9.2. MS (FAB) m / e 790 (M + H) + 812 (M + Na) +, 828 (M + K) +. High Resolution Mass Spectrum m / z calculated for C40H7.NO? 4K: 828.4512. Found: 828.4516.eVe
EXAMPLE 5 COMPOSITE FORMULA (X): X ES = O, R ES 2-HYDROXY-3- (IMIDAZOL-1 -IL) PROPYL. To a solution at room temperature of the compound resulting from Example 4 (100 mg) in 1 mL of chloroform were added 17 mg of imidazole. The reaction vessel was sealed and then stirred at room temperature for one hour. Two additional equivalents of imidazole were added, and was then stirred for sal days. The solvent was removed under reduced pressure, and the crude material obtained was purified by column chromatography eluted with 5% MeOH in methylene chloride containing 1% NH OH to give 44 mg (41%) of the reference compound. C13 NMR (CDCl 3) epimer mixture d 223.3, 221.2 (C-9), 176.4, 175.9 (C-1), 137.9 (C-19), 128.7 (C-120), 120.1 (C-21), 1 19.9, 102.2, 102.1 (C-1 '), 96.5 (C-1"), 80.3, 79.7, 79.2, 78.9, 77.6, 77.6, 77.4, 77.2, 77.0, 77.0, 76.7, 74.7, 74.6, 72.7, 72.7 , 71 .0, 69.7, 69.4, 69.0, 69.0, 68.5, 68.5, 66.8 (C-16), 66.0, 65.5, 65.4, 50.2 (C-18), 49.3 (C-18), 49.3 (C-3" -OMe), 45.5 (C-2), 45.2 (C-2), 44.7 (C-8), 44.7 (C-8), 40.1 (-NMe2), 38.2 (C-7), 38.1 (C-7) ), 37.8, 37.5, 34.9 (C-2"), 28.4 (C-4 '), 21.6, 21.4, 21.3, 21.3, 21.2, 20.9, 20.8, 18.9, 18.8, 18.7, 18.6, 16.2, 16.1 (C-2 Me, C-6 Me), 16.0, 1 1.9 (C-10 Me), 1 1.9, 10.4 (C-15), 10.4, 9.3 (C-4 Me). / z 858 (M + H) + High Resolution Mass Spectrum m / z calculated for C 3 H 76 N 3 O 4: 858.5327 Found: 858.5320.
EXAMPLE 6 COMPOSITE FORMULA (X): X ES = O, R, ES 2-HYDROXY-3- (MORPHOLINE-4-IL) PROPYL.
To a solution at room temperature of the compound resulting from Example 4 (100 mg) in one mL of chloroform was added 22 μL of morpholine. The reaction vessel was sealed and stirring was continued at room temperature for one hour. Two additional equivalents of morpholine were added and stirring was continued for sal days. The solvent was removed under reduced pressure, and the crude material obtained was chromatographed on silica gel eluted with 3% MeOH in methylene chloride containing 1% NH4OH to give 35mg (33%) of the reference compound. C13 NMR (CDCl 3) epimer mixture d 220.3, 219.1 (C-9), 176.1, 175.5 (C-1), 102.1, 102.1 (C-1 '), 96.2, 96.1 (C-1"), 80.0, 79.8 , 79.7, 79.1, 78.6, 78.6, 77.8, 77.7, 77.3, 77.1, 77.0, 76.7, 76.6, 75.0, 75.0, 72.8, 71.0, 68.5, 68.2, 67.8, 67.0, 66.9 (C-21, 22), 66.4, 66.00, 65.9,
65. 5, 65.5, 61.4 (C-18), 60.8 (C-18), 60.3, 53.9, 53.8, 51.9, 49.3, 49.3 (-OMe), 46.4, 45.5, 45.4 (C-2), 44.8, 44.7 (C-8), 40.2 (-NMe2), 38.3 (C-10, 4), 38.2, 38.1, 37.9 (C-7), 37.7, 35.0, 29.6, 28.5 (C-4 '), 21 .7, 21.5, 21.4, 21.4, 21.3, 21.3 (C-14, 3"-Me, 6'-Me), 21.1, 20.9, 19.0, 18.7 (C-8 Me, C-6 'Me),
18. 6, 16.3, 16.2, 16.0 (C-2 Me, 6 Me), 16.0, 14.1, 12.1 (C-10 Me), 10.6, 10.5 (C-15), 9.3 (C-4 Me). MS (FAB) m / e 877 (M + H) +, 915 (M + K) +.
EXAMPLE 7 COMPOSITE FORMULA (X): X ES = O, R ES 2-HYDROXY-3-BENZYLAMINE) PROPYL. To a solution at room temperature of the compound resulting from Example 4 (40 mg) in 1.5 mL of chloroform were added three equivalents (58 μL) of benzylamine. The reaction mixture was stirred overnight at room temperature and then heated at 62 ° C for about three hours and then stirred overnight at room temperature. The reaction mixture was then heated at 70 ° C for two hours and then concentrated in vacuo. The residue was quenched twice with toluene to give 170 mg of crude reference compound. The crude product was purified by silica gel chromatography eluted with 2% MeOH in methylene chloride containing 1% NH 4 OH to give the reference compound as a mixture of epoxide epimers. C13NMR (CDCI3) d 221.7, 220.1 (C-9), 176.4 (C-1), 175.7, 140.7 (C-20), 140.5, 128.5, 128.2, 128.1, 128.1, 127.0, 126.7, 126.6, 126.5, 102.2 ( C-1 1), 96.2 (C-1"), 79.9, 79.6, 79.3, 78.8, 78.7, 77.6, 77.6, 76.8, 76.7, 74.9, 72.7, 72.7, 71 .0, 69.7, 69.1, 68.7, 68.5, 67.9, 67.8 (C-16), 66.04, 65.6, 53.8, 53.6, 51.6, 51.3, 49.3 (-OCH3), 45.5 (C-2), 45.4, 44.7, 44.6 (C-8), 40.2 (- NMe2), 38.2, 38.2 (C-7), 38.0 (C-10.4), 37.9, 35.0, 34.8 (0-2"), 28.5 (C-45), 21.7, 21.4, 21.4, 21 .1, 21 .1, 18.9, 18.6, 18.6, 16.2, 16.2, 16.0, 15.9, 12 1, 12.0 (C-10CH3), 10.5 (C-15), 9.3 (C-4CH3), 9.3. MS m / z 897 (M + H) +.
EXAMPLE 8 COMPOSED FORMULA (X): X ES = O, R ES 2-HOXOETHYL. To a solution of the compound resulting from example 3 (275 mg) in
6. 5 mL of a 20% aqueous THF were added 87mg of Nal0. The reaction was stirred at room temperature for two hours and then 0.5 equivalents of NalO 4 were added. After two additional hours, another 0.5 equivalents of NalO4 were added. After two more hours, the reaction mixture was filtered through a plug of NH4OH to give 195 mg (65%) of the reference compound. C 13 NMR (CDCl 3) d 221.0 (C-9), 203.2 (CHO), 175.5 (C-1), 102.4 (C-1 '), 101.9, 96.7, 96.3 (C-1"), 96.0, 80.5, 79.8, 78.5, 77.7, 76.7, 74.5 (C-12), 72.7 (C-3"), 71.1, 70.3, 68.9, 68.7, 68.0, 66.4, 66.1, 65.6, 49.4 (C-3" OMe), 45.8, 44.9, 44.7, 41.0, 40.2 (NMe2), 38.4 (C-4), 38.2 (C-7), 37.9, 37.4 (C-10), 35.1, 34.9 (C-2"), 28.5 (C-4 '), 21.7, (21.5, 21.4, 21 .1 (C-3"Me, 6Me)), 21.0 (C-17), (18.8, 18.6, 18.5 (C-8Me, 6" Me)), 16.3, 16.0 (C -2Me), 12.2 (C-10Me), 12.1, 10.4 (C-15), 9.3, 9.2 (C-4Me). Expectrum of Mass m / z 776 (M + H) +.
EXAMPLE 9 COMPOSITE FORMULA (X): X ES = O, R ES 2-OXOPROPILO A mixture of 1.5mL of 7: 1 DMF-H2O, 5mg PdCI2 and 21 mg of CuCl was stirred under an atmosphere of oxygen for ~ 1.33 hours . To this mixture was added a solution of the compound resulting from example 1 (150 mg) in 1.5 mL of 7: 1 DMF-H2O by dripping for 10 minutes. The reaction mixture was heated to 50 ° C and maintained at that temperature for about 1 hour and at room temperature overnight. Additional aliquots of PdCI2 (5mg) and CuCl (21mg) were added. The reaction mixture was heated to 54 ° C and maintained at that temperature for approximately 3 hours. The reaction mixture was allowed to cool to room temperature and then O2 was bubbled through the reaction mixture which was stirred overnight at room temperature. ) and additional CuCl (42mg), and O2 was continued. The reaction mixture was heated to 40 ° C for about three hours and then stirred over the weekend at room temperature. The reaction mixture was diluted with EtOAc and washed twice with 30% aqueous ammonium hydroxide solution and twice with brine, dried over SgSO4 and concentrated in vacuo to give 85 mg of crude reference product. Purification by elution through a plug of silica gel with 1% MeOH in methylene chloride containing 1% ammonium hydroxide gave 47 mg of the reference compound. C13NMR (CDCI3) d 217.9, 205.3, 175.0, 102.9, 102.4, 101.8, 96.5, 95.9, 94.7, 80.6, 79.0, 78.9, 78.2, 77.7, 77.5, 77.3, 77.0,
76. 8, 76.7, 75.1, 72.7, 71.2, 71.0, 70.8, 70.5, 69.6, 68.8, 68.7, 68.3, 66.1,
65. 9, 65.6, 49.5, 49.4, 45.1, 44.8, 43.3, 42.7, 40.3, 40.2, 38.4, 37.6, 35.0, 34.7, 30.4, 28.7, 28.5, 26.5, 26.2, 25.9, 21.5, 21.4, 21.3, 21.3, 21.1, 19.2,
18. 7, 18.3, 16.2, 15.9, 14.8, 13.6, 12.2, 1 1 .9, 10.9, 10.6, 9.3, 8.7. High Resolution Mass Spec (FAB) calculated for m / z (M + H) + C 0H72NO12: 790.4953. found m / z 790.4932).
EXAMPLE 10 COMPOSED FORMULA (X): X ES = O, R ES -CH2-C = CH. EXAMPLE 10A COMPOSED OF FORMULA (X): X ES = N-O- (1-ISOPROPOXICICLOHEXYL), R ES -CH2-C = CH. A solution of 1.14g of powdered KOH in 30mL of anhydrous DMSO and 30mL of freshly distilled anhydrous THF were added via addition with a funnel to a solution at 0 ° C of the compound of the formula
XII wherein X is = N-O- (1-isopropoxycyclohexyl) and Rp is trimethylsilyl (10g) in 60 mL of 1: 1 DMSO-THF. This was followed by a solution containing 2.38 mL of propargyl bromide (80%) in added toluene for 10-15 minutes. The reaction mixture was stirred at 0 ° C for about 1 hour and then two additional equivalents of propargyl bromide were added at 0 ° C. After two hours, two equivalents of pulverized KOH (~ 1g) were added at 0 ° C, and the reaction mixture was placed in the refrigerator overnight. The next day an additional 4 mL of propargyl bromide was added at 0 ° C. When the tic indicated that the reaction was complete, the reaction was quenched with 10 equivalents of allylamine at 0 ° C and stirred for 5 minutes. The diluent in the mixture was H2O and EtOAc and the organic layer was washed with water followed twice with brine. The organic layer was dried over MgSO and concentrated under reduced pressure to give 11.5 g of crude reference compound. Filtration through a plug of silica gel eluted with 10% acetone in hexane containing 0.25% Et3N-9.3 of purified reference compound.
EXAMPLE 10D COMPOSED OF FORMULA (X): R ES -CH2-C = CH, X ES = N-O-H. To the resulting compound of Example 10A (9.3g) in 50mL of acetonitrile and 35mL of water were added 50mL of HOAc. The reaction mixture was stirred in the dark at room temperature for two hours and placed in the refrigerator overnight. The reaction mixture was allowed to warm to room temperature, diluted with toluene and concentrated in vacuo. The obtained residue was used without further purification.
EXAMPLE 10C COMPOSED OF FORMULA (X): X ES = O, R ES -CH2-C- = CH. The resulting compound of Example 10B (8.16g) in 1: 1 EtOH-H 2 O (140ml) was treated with four equivalents of NaHSO 3 and formic acid (960μL, 2.4 equivalents) and heated to ~ 82 ° C. After about 2.5 hours, the reaction mixture was allowed to cool to room temperature, it was basified to pH 10 with 1 N NaOH solution and extracted with EtOAc. The combined organic extracts were washed, dried and concentrated in vacuo. The obtained crude product was chromatographed on silica gel eluted with 1% MeOH in methylene chloride containing 1% ammonium hydroxide to give 2.9 g (40%) of the reference compound which was recrystallized from acetonitrile. C13 NMR (CDCl 3) d 219.7 (C-9), 175.2 (C-1), 151.7, 104.4. 103.0, 102.6 (C-1 '), 101.5, 96.2 (C-1"), 95.9, 94.6, 92.0, 85.6, 81.2, 81.1, 80.7 (C-5), 80.3 (C-6), 80.1, 78.8 ( C-3), 78.2, 78.1, 77.9 (C-4"), 77.3, 77.3, 77.0, 77.0, 76.8, 76.7, 76.6, 76.3, 75.3, 74.5 (C-17), 73.9 (C-12), 72.7 , 71 .0 (C-1 1), 70.8, 70.0, 69.3, 68.8, 68.7 (C-5 '), 65.9, 65.8, 65.6, 65.5, 65.0, 51.8 (C-16), 49.5, 49.4 ( C-3'OMe), 45.2 (C-2), 44.8 (C-8), 44.7, 43.3, 42.6, 40.3, 40.2 (NMe2), 39.3, 38.6 (C-7), 38.5 (C-4), 37.5 (C-10), 35.0 (C-2"), 34.6, 30.5, 29.4, 28.7, 28.6 (C-4 '), 26.2, 25.8, 23.9, 22.6, 21.5 (C-3" Me, 6' Me ), 21 .3, 21.2 (C-14), 21.0 (C-3"Me, 6 'Me), (18.7, 18.4 (C-2 Me, 6 Me)), 18.3, 18.2, 17.6, 16.1, 16.0 , 15.0, 14.8, 13.7, 13.4, 13.1, 12.3 (C-10 Me), 1 1 .9, 1 1 .2, 10.9, 10.6 (C-15), 9.2 (C-4Me), 8.7 MS (FAB) ) m / e 772 (M + H) \ 810 (N + K) +.
EXAMPLE 11 COMPOSED FORMULA (X): X ES = O, Re-CH2-CHOH-CH2-N3. To a solution at room temperature of the compound resulting from Example 4 (100mg) in 0.65mL DMF was added 12mg of NaN3. The reaction mixture was stirred at room temperature for about 5.5 hours and then 8 milligrams of additional NaN3 was added. The reaction mixture was stirred at room temperature overnight, heated at 70 ° C-90 ° C for 3 hours and then treated with an additional 14mg of NaN3. The reaction mixture was heated at 60 ° C for one night. 4 drops of water were added, and the reaction mixture was heated at 80 ° C for 4 hours. One equivalent of ammonium chloride was added and heating was continued at 80 ° C for two hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with NaOHO.dN solution and brine, dried and concentrated in vacuo. The residue obtained was filtered through a plug of silica gel eluted with 4% MeOH in methylene chloride containing 1% ammonium hydroxide to give 47 mg (50%) of the reference compound containing trace amounts of DMF. The DMF was removed by dissolving the compound in EtOAc-Et 2 O 1: 1, washing with water followed by brine, drying over magnesium sulfate and concentrating vacuo to give 45 mg of the reference compound which was further purified by filtering through silica eluting with 4% MeOH in methylene chloride containing 1% ammonium hydroxide to give the reference compound. C 3NMR (CDCl 3) mixture of delta epimers 222.8, 221.2 (C-9), 176.6, 78.9, 78.7, 77.6, 77.5, 77.4, 77.0, 76.6. 74.8, 74.7, 72.8, 71.0IC-11), 70.0, 69.7, 68.9, 68.6, 67.3, 66.8, 66.2, 65.8, 65.6, 53.8, 53.2 (C-18), 49.3 (C-3"OMe), 45.6 ( C-2), 45.4, 44.7 (C-8), 42.0, 40.2 (-NMe2), 38.4, 38.2, 37.9, 37.6, (35.1, 35.0 (C-2")) t 29.6, 28.5 (C-4 ') ), 23.0, 21.8, 21.5, 21.2, (21.1, 21.0 (C-14)), 20.9, 18.8, 18.2, 16.1, 12.0 (C-10Me), 12.0, 11.0, 10.4 (C-15), 10.1, 9.3 , 9.3 (C-4Me), 8.6. MS (FAB) m / e 833 (M + H)? 871 (M + K) +. Expectro of High Resolution Mass m / z (M + H) + calculated for C 0H73N O? 4: 833.5123. Found: 833.5137.EXAMPLE 12 COMPOSED FORMULA (X): X IS O, R ES -CH2-CH = N-OH. To a solution of the compound resulting from Example 8 (600mg) in 5mL of MeOH was added a solution of 80mg of hydroxylamine hydrochloride and 255μL of N-methylformolin in two mL of MeOH. The reaction mixture was stirred at room temperature for 5 hours and then concentrated in vacuo. The obtained residue was purified by elution from silica gel using 4% MeOH in methylene chloride containing 1% ammonium hydroxide to give the reference compound as a 1: 1 mixture of oxime isomers. C13 NMR (CDCl 3) d 220.8, 219.9 (C-9), 175.4, 175.3 (C-1), 151.7 (CH = N), 149.2 (CH = N), 102.4, 102.3 (C-1 '), 96.3 ( C-1"), 92.0, 86.6, 80.0, 80.0, 79.9, 79.8, 78.8, 78.8, 77.7, 77.3, 77.0, 76.7, 76.5, 76.4, 74.5, 74.4 (C-12), 72.7 (C-3") , 72.7, 71 .1, 68.8, 68.7, 68.5, 68.5, 66.6, 66.0, 65.9, 65.6, 65.4, 65.0, 61.4, 58.6, 55.2, 49.4, 49.3, 49.4, 49.3, 45.2, 45.2, 45.2, 45.2, 45.2, 45.2, 45.2, 45.2, 45.2, 45.2, 45.2, 45.2, 45.2 , 44.6, 40.3, 40.2 (-NMe2), 39.2 (38.4, 38.3 (C-4)), 38.2 (C-7), 37.4, 37.2 (C-10), 35.0 (C-2"), 28.6 (C -4 '), 24.8, 23.0, 21.6, 21.4, 21.4, 21.2, 21.1, 21.0, 20.9, 20.5, 18.7, 18.6, (18.4, 18.4 (C-8Me, 6"Me)), 18.2, 17.7, 16.1, 16.0, 16.0 (C-2Me), 15.9, 12.2 (C-10Me), 10.4 (C-15), 9.2 (C-4Me), MS m / z 791 (M + H) +.
EXAMPLE 13 COMPOSITE FORMULA (X): X ES = O, R ES -CH2-CH2OH. To a solution at minus 78 ° C of the compound resulting from Example 8 (75mg) in one mL of anhydrous THF was added 1.1 equivalents of L-Selectride per drop for two minutes. The reaction mixture was stirred at -78 ° C for about 1 hour and then turned off at -78 ° C with an aqueous solution of tris-hydroxymethylaminomethane followed by EtOAc. The organic phase was washed twice with brine, dried over magnesium sulfate and concentrated in vacuo. The raw material (76 mg) was chromatographed on silica gel eluted with 3% MeOh in methylene chloride containing 1% ammonium hydroxide to give 20 milligrams of the desired reference compound. C 13 NMR (CDCl 3) d 221. 1 (C-9, 215.7, 203.2, 176.7, 175.9 (C-1), 175.5, 102.7, 102.4, 102.1, 96.6, 96.3, 83.8, 80.4, 80.2, 80.0, 79.8, 79.6, 79.4, 79.2, 78.8, 77.7 , 77.4, 77.0, 76.6, 74.8, 74.5, 72.8, 72.7, 71.1, 70.3, 68.8, 68.5, 66.1, 66.0, 65.6, 65.4, 62.3, 62.0, 49.4, 45.6, 45.4, 44.7, 42.0, 41 .1 , 40.2 (NMe2), 39.4, 38.6, 38.1, 37.8, 37.4, 35.1 (C-2"), 28.8, 28.5 (C-4 '), 25.9, 23.5, 21.8, 21.6, 21.5, 21.0, 18.7, 18.6, 18.5, 16.2, 15.4, 15.1, 14.4, 13.3, 12.1, 11.8, 10.5, 9.4 MS m / e 778 (M + H) +.
EXAMPLE 14 COMPOSED FORMULA (X): X ES = O, R ES -CH2-CH2NH2.
The resulting compound of Example 12 (160 mg) was subjected to catalytic hydrogenation using a Ranei nickel catalyst under four atmospheres of hydrogen for 20 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 159 mg of crude reference compound. Purification by silica gel column chromatography eluted with 7% MeOH in methylene chloride containing 1% ammonium hydroxide gave 87 mg (55%) of the reference compound. C13NMR (CDCl3) d 219.9 (d9), 175.5, C-1), 101.6 (C-1 '), 96.1 (C-1"), 79.3 (C-5), 78.9 (C-3), 78.4 (C-6), 77.3 (C-4"), 77.0, 76.7, 76.3 (C-13), 74.8 (C-12), 72.5 (C-3"), 71 .1 (C-1 1), (68.0, 67.7, 65.6, 64.4, 64.2 (C-2 ', 3', 5", 5 ', 16)), 48.8 (C-3" OMe), 48.7, 48.5, 48.4, 48.2, 48.0, 47.9, 47.7, 45.0 (C-2), 44.4, 40.6, 39.6, (NM? 2), (37.9, 37.8 (C-4), 10)), 37.5 (C-7), 34.8 (C-2"), 29.0 (C-4 '), 21 .0, 20.9, 20.8 (C-17), 20.7, (18.4, 18.1 (C-8Me), 6"Me), (15.9, 15.4 (C-2Me, 6Me), 1 1.4 (C-10Me), 10.0 (C-15), 9.0 (C-4Me), MS m / z 777 (M + H) +.
EXAMPLE 15 COMPOSED FORMULA (X): X ES = O, R ES -CH2-CN. To a solution of the resultant compound of Example 12 (165mg) in 15mL of freshly distilled THF were added two equivalents of diisopropylcarbodiimide (65μL) followed by a catalytic amount of CuCl. After stirring for about 2 hours at room temperature, two additional aliquots of diisopropylcarbodiimide (65μL) plus additional CuCl were added. After 3 more hours, the reaction was complete and the solvent was removed in vacuo to give the reference compound.
Expectrum of Mass m / z 773 (M + H) +.
EXAMPLE 16 FORMULA COMPOUND (X): X ES = O, R ES -CH2-PHENYL EXAMPLE 16A COMPOSED OF FORMULA (XII): X ES = NO- (1-ISOPROPOXICICLOHEXYL), R ES -CH2-PHENYL, Rp ES TRIMETILSILIL . To a solution at 0 ° C of 30mL of a 1: 1 solution of THF and DMSO containing 5g of the compound of formula (X) wherein X is = NO- (1-isopropoxycyclohexyl) and R is hydrogen were added 1.2mL of benzyl bromide. A second solution of 30mL of DMSO and THF 1: 1 containing 560mg of pulverized KOH were added in portions for 45 minutes at 0 ° C with good agitation. At the end of the addition, it was stirred at 0 ° C under nitrogen for 1 hour and then halilamine (700μL) and ethyl acetate were added. The solution was washed with water and brine (2x), dried over magnesium sulfate, filtered and concentrated in vacuo to give 6g of the reference compound.
EXAMPLE 16B COMPOSED OF FORMULA (XII): X ES = NO- (1-ISOPROPOXICICLOHEXYL), R-CH2-PHENYL, Rp is H. To a solution at room temperature of 6g of the compound resulting from Example 16A in 65mL of anhydrous THF is they added 14.5mL of tetrabutylammonium fluoride 1 M_- After several hours, the solvent was removed under reduced pressure and the residue was dried at constant weight. Purification by column chromatography eluted with 4% methanol in methylene chloride containing 1% ammonium hydroxide gave 2.8.
EXAMPLE 16C COMPOSED FROM FORMULA (XII): X ES = N-OH, R ES -CH2-RP is H. To the compound resulting from Example 16B (2.8g) in 26mL of acetonitrile were added 14mL of water followed by 14mL of acetic acid. . The reaction mixture was stirred for ~ 4 hours at room temperature and then placed in the freezer overnight. The volatiles were removed in vacuo, and the residue was quenched twice with toluene and dried to constant weight to give 2.73g of the reference compound.
EXAMPLE 16D COMPOSED OF FORMULA (X): X ES = O, R ES - CH2-PHENYL To the resulting compound of Example 16C (2.7g) in 23mL of EtOH and water (23mL) were added 1.4g of NaHSO3. This was followed by 292μL of formic acid, and the reaction mixture was heated to 80 ° C. After approximately 90 minutes, the reaction mixture was allowed to cool to room temperature, basified to pH 10-1, with 2N NaOH solution and extracted with ethyl acetate.The combined organic extracts were washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated in vacuo The crude material (1.95g) was chromatographed on silica gel eluted with 1% methanol in methylene chloride containing 1% ammonium hydroxide followed by 2% methanol. in methylene chloride containing 1% ammonium hydroxide to give 715mg of the reference compound The additional purification was carried out by chromatography on silica gel eluted with 2% ammonium hydroxide in methylene chloride followed by 2% methanol in chloride of methylene containing 1% ammonium hydroxide to give 435mg of the reference compound C13 NMR (CDCI3) d 219.28, 174.69, 139.20, 128.51, 127.95, 127.12, 102.20, 96.42, 80.14, 79.8, 78.9 6, 77.79, 77.42, 77.00, 76.56, 74.77, 72.84, 71.1, 1, 68.75, 68.56, 66.39, 66.31, 65.61, 49.41, 45.15, 44.62, 40.27, 38.02, 37.91, 35.19, 28.54, 21.95, 21.56 , 21.53, 21.28, 19.2, 18.82, 16.25, 16.09, 12.24, 10.61, 9.56. MS (FAB) m / e 824 (M + H) +.
EXAMPLE 17 COMPOSED FORMULA (X): X ES = O, R ES -CH2-CH = CH (PHENYL). The reference compound was prepared by the procedures described in Example 16 by substituting 3-phenylalkyl bromide for benzyl bromide. For conversion of the oxime to the ketone, the reaction mixture was heated for about 3 hours then placed in the freezer overnight. Chromatography on silica gel eluted with 1% methanol in methylene chloride containing 1% ammonium hydroxide gave ~ 700 mg (17% yield by three steps) of the reference compound.
EXAMPLE 18 COMPOSITE FORMULA (X): X ES = O, R ES -CH2-CH = N-0-CH3.
To a room temperature solution of 150 mg of the compound resulting from Example 8 in 1 mL of methanol was added a solution of 14 mg of methoxylamine hydrochloride in 0.5 mL of methanol containing 64 μL of N-methylmorpholine in one portion. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for about 6 hours and then treated with 0.75 equivalents (12 mg) of methoxylamine hydrochloride. The reaction mixture was stirred at room temperature for 1 hour and then placed in the refrigerator overnight. The volatiles were removed under reduced pressure to give 215 mg of crude reference compound. Purification by silica gel column chromatography eluted with 1% methanol in methylene chloride containing 1% ammonium hydroxide gave 120 mg (78%) of the reference compound as a 1: 1 mixture of syn: anti. C 3NMR (CDCI3) d 219.3, 218.4, 173.8, 173.7, 157.9, 157.9, 149.5, 146.8, 100.8, 100.7, 94.7, 94.5, 93.0, 78.4, 78.2, 77.3, 77.1, 76.2, 75.9, 75.4, 75.0, 74.9, 74.8, 72.9,
72. 7, 71.2, 71.1, 69.4, 67.2, 67.1, 67.0, 65.3, 64.5, 64.4, 64.0, 59.9, 57.3,
47. 8, 47.8, 44.8, 43.7, 43.6, 43.0, 38.6, 36.8, 36.7, 36.7, 35.7, 33.4, 26.9,
19. 9, 19.8, 19.4, 18.9, 17.1, 16.9, 16.8, 14.4, 14.4, 10.6, 8.9, 8.8, 7.6, 7.5. MS (FAB) m / e 805 (M + H) +.
EXAMPLE 19 FORMULA COMPOSITE (X): X ES = O, R ES -CH2-CH = NO-CH2-PHENYL The reference compound was prepared as a 1: 1 syn: anty mixture by the procedures described in Example 18 Substituting O-benzylhydroxylamine hydrochloride for methoxylamine hydrochloride to give 118 mg (70%). C13 NMR (CDCl 3) d 219.3, 218.5, 173.8, 173.7, 157.8, 149.8, 147.6, 136.6, 126.5, 126.5, 126.2, 125.8, 125.8, 100.8, 100.8, 94.7, 94.5, 94.3, 78.5, 78.4, 78.2, 77.2, 76.2, 76.2, 75.8, 75.4, 75.0, 74.9, 74.2, 74.0, 72.8, 72.7, 71.2, 71.1, 69.4, 67.2, 67.1, 67.0, 65.3, 64.4, 64.4, 64.4, 60.1, 57.5, 53.8, 47.8, 47.8, 44.8, 43.6, 43.0, 38.6, 36.8, 36.8, 36.7, 36.7, 35.6, 33.4, 33.4, 26.9, 19.9, 19.8, 19.8, 19.8, 19.8, 19.8, 19.8, 19.4, 19.4, 19.4, 19.8, 19.8, 19.8, 19.8, 19.8, 19.4, 19.4, 17.4, 14.4, 14.4, 14.4, 14.6, 10.6, 10.6, 8.9, 7.6. MS (FAB) m / e 881 (M + H) +.
EXAMPLE 20 COMPOSITE FORMULA (X): X ES = O, R ES -CH2-CH = NN (CH3) 2 The reference compound was prepared by the procedures described in Example 18 substituting N, N-dimethylhydrazine for methoxylamine hydrochloride . Purification by column chromatography eluted with 2% methanol in methylene chloride containing 1% ammonium hydroxide gave 115 mg (73%) of the reference compound as a single isomer (syn or anti). C13 NMR (CDCl 3) d 217.8, 173.5, 157.6, 132.4, 100.5, 94.5, 92.7, 78.1, 77.4, 76.0, 75.6, 75.2, 74.7, 74.6, 72.6, 70.9, 69.2, 66.7, 64.1, 63.7, 63.0, 47.5, 43.4, 42.7, 41.0, 38.4, 36.6, 36.5, 35.4, 33.1, 26.7, 19.6, 19.6, 19.4, 19.2, 16.8, 16.6, 14.3, 14.0, 10.4, 8.8, 7.4. MS (FAB) m / e 818 (M + H) +.
EXAMPLE 21 COMPOSITE FORMULA (X): X ES = O, R ES -CH2-CH = N-NH (CH3) The reference compound was prepared by the procedures described in Example 18 substituting N-methylhydrazine for methoxylamine hydrochloride. Purification by column chromatography eluted with 2% methanol in methylene chloride containing 1% ammonium hydroxide gave 89 mg (58%) of the reference compound as a pure, simple isomer of unknown stereochemistry. C13NMR (CDCI3) d 219.7, 175.5, 136.2, 102.5, 96.5, 80.1, 79.4, 79.1, 77.9, 77.2, 77.0, 76.7, 76.5, 74.5, 72.8, 71.1, 68.7, 66.1, 65.7, 64.4, 49.4, 45.3, 44.6 , 40.3, 38.6, 38.5, 37.4, 35.1, 34.8, 28.6, 21.5, 21.5, 21.3, 21.0, 18.8, 18.5, 16.2, 15.9, 12.3, 10.7, 9.2. MS (FAB) m / e 804 (M + H) +.
EXAMPLE 22 FORMULA COMPOUND (X): X ES = O, R ES -CH2-CH = N- (4-MORFOLINIL). The reference compound was prepared by the procedures described in Example 18 substituting N-aminomorpholine for methoxylamine hydrochloride. Purification by column chromatography eluted with 5% methanol in methylene chloride containing 1% ammonium hydroxide followed by rechromatography eluted with 2% methanol in methylene chloride containing 1% ammonium hydroxide gave 125mg (75% ) of the reference compound as a pure, simple isomer of unknown stereochemistry. Diagnostic peaks H1 NMR (CDCI3), 500 MHz) d 0.84 (t3H), 2:29 (S6H), 3.12 (m 4H), 3.34 (s 3H), 3.85 (t 4H), 4.50 (d 1 H), 4.92 (d, 1 H), 5.06 (d of d, 1 H). MS (FAB) m / e 860 (M + H) +.
EXAMPLE 23 COMPOSITE FORMULA (X): X ES = O, R ES -CH2-CH = N-NH (PHENYL)
The reference compound was prepared by the procedures described in Example 18 by substituting N-phenylhydrazine for methoxylamine hydrochloride. Purification by column chromatography eluted with 1% methanol in methylene chloride containing 1% ammonium hydroxide gave 50 mg of the reference compound as a simple isomer 1 of unknown stereochemistry. 1MS (FAB) m / e 866 (M + H) +.
EXAMPLE 24 FORMULA COMPOUND (X): X ES = O, R ES -CH2-CH = N-N (PHENYL) 2
The reference compound was prepared by the procedures described in Example 18 by substituting N, N-diphenylhydrazine for methoxylamine hydrochloride. Purification by column chromatography eluted with 2% methanol in methylene chloride containing 1% ammonium hydroxide gave 156 mg of the reference compound as a pure, simple isomer of unknown stereochemistry. Diagnostic peaks H1 NMR (CDCI3), 300MHz) d 7.07-7.39 (m, 10H), (m,
6. 46 (t1 H). MS (FAB) m / e 942 (M + H) +.
EXAMPLE 25-75 Using the procedures described in the preceding examples and schemes and methods known in the art of synthetic organic chemistry, the following compounds can be prepared.
Ex. No. Structure of R 25"OH
27 H 'CH3
28 H • N ^ CHa
29 .H, .Pt
CHg CHa
31
36 CHs
37 CH3
38 CH3 CHg
39
40 'Ph
42 OH3
43, CH3 44 45 ^ .CHg 46 47 ^ l
48 CHg 49 .CHO
55 'COaCHj
56 CH3
57 58 'CHa
61
67 N02
69, CH3
70 NH, ^ Y
73 a
EXAMPLES 76-107 Using the procedures described in the preceding examples and schemes and methods known in the art of organic chemical synthesis, the following compounds can be prepared. The macrolide ring systems are selected from the group consisting of:
fifteen
where A, B, D, E, W, X, Y, Z, R, Ra, Rb, R °, Rd, Re, Rf, Rg, and Rh are as previously defined.
79 2-Fluoroethyl bromide
80 4-Nitrobenzy 1 bromide
8 4-Chlorabenzyl bromide
82 4-Methoxybcnzyl bromide
83 a-Bromo-p-tolunitrilc
84 Cinnamyl bromide
85 Methyl 4-bromocrotonate 'C02C- ^
86 Crotyl bromide 'CH3
87 l-Bromo-2-pentene. CH3
88 3-Bromo-l-ptopenyl phenyl sulfone O 89 3-Bromo-l-trimethyisilyl-1-propyne
90 3-B? Ano-2-octype
91 I-Bromo-2-butyne
92 2-Kcolyl chioride
93 3-Picolyl choride
94 4-PicoIyl chioride
95 4-Bromomethyl quinoline
96 Bromoacetonitrile x ^ Nv ^ .N
97 Epichlorohydrin '~ Ns < 1 o
98 Bromofluoromethane ^ 9 Bromonitronr-ethane * • "^ NO2
100 Methyl bromoacetate
101 Methoxymethyl chioride -CHa
102 Bromoacetamide
103 2-Bromoacetophenone
104 l-Bromo-2-butanone
105 Bromo chlaromethane Cl
106 Bromsmethyl phenyl s? Lfone
107 1 -Dibromo-l -propene Br EXAMPLE 62 In Vitro Antibacterial Activity Test The representative compounds of the present invention were tested in vitro for antibacterial activity as follows: Twelve petri dishes containing successive aqueous solutions of the test compound mixed with 10 mL of Brain Heart Infusion agar
(BHI) (Difco 0418-01-5) sterilized. Each box was inoculated with dilutions
1: 100 (or 1: 10 for slow-growing layers, such as Micrococcus and
Streptococcus) of up to 32 different microorganisms, using a Steers duplicator block. The inoculated plates were incubated at 35-37 ° C for 20-24 hours. In addition, a control box, using BHI agar that did not contain test compound, was prepared and incubated at the beginning and end of each test. An additional plate containing a compound having known susceptibility standards for organisms that are tested and belonging to the same class of antibiotic as the test compound was prepared and also incubated as an additional control, as well as to provide test comparability. a-test. Erythromycin A was used for this purpose. After incubation, each plate was visually inspected.
The minimum inhibitory concentration (MIC) was defined as the lowest concentration of drug that gives colonies without growth, a light veil, or barely isolated at the inoculated point compared to the growth control. The results of this test, shown below in Table 2, demonstrate the antibacterial activity of the compounds of the invention.
Table 2 Antibacterial Activity (MIC's) of Selected Compounds
Microorganism Erv. A Example IB Example IC Staphyfococcus aureus ATCC 6538P 0.2 0.78 0.78
Staphylococcus aureus A5177 3.1 12.5 12.5
Staphylococcus aureus A-5278 > 100 > 100 > 100
Staphylococcus aureus CMX 642A 0.39 1.56 1.56
Staphylococcus aureus NCTC10649M 0 0..3399 3.1 0.78 Staphylococcus aureus CMX 553 0.39 1.56 0.78
Staphylococcus aureus 1775 > 100 > 100 > 100
Staphylococcus epidermidis 3519 0.39 0.39 0.39
Enterococcus faecium ATCC 8043 0.05 0.2 0.2
Streptococcus bovis A-5169 0.02 0.02 0.01 Streptococcus agalactiae CMX 508 0.05 0.1 0.01
Streptococcus pyogenes EES61 Streptococcus pyogenes 930 > 100 > 100 > 100
Streptococcus pyogenes PIU 2548 3.1 6.2 3.1
Micrococcus luteus ATCC 9341 0.05 0.2 0.1 Micrococcus luteus ATCC 4698 0.2 3.1 1.56
Staphylococcus aureus CMX 553 0.39 0.78 0.78
Staphylococcus aureus 1775 > 100 > 100 > 100
Staphylococcus epidermidis 3519 0.39 1.56 0.78
Enterococcusfaecium ATCC 8043 0.05 0.39 0.39 Streptococcus bovis A-5169 0.02 0.05 _ Antibacterial Activity (MIC's) of Selected Compounds (Contd)
Microorganisms Ery. A Example 7 Example 8 Streptococcus agalactiae CMX 508 0.05 0.1 0.1 Streptococcus pyogenes EES61 - 0.05 0.05 Streptococcus pyogenes 930 > 100 > 100 > 100 Streptococcus pyogenes PIU 2548 3.1 - 6.2 Micrococcus luteus ATCC 9341 0.05 0.1 0.1 Micrococcus luteus ATCC 4698 0.2 3.1 1.56 Escherichia coli JUHL > 100 25 > 100 Escherichia coli SS 0.78 0.78 0.78 Escherichia coli DC-2 > 100 50 > 100 Escherichia coli H560 50 50 I00 Escherichia coli KNK 437 100 50 > 100 Enterobacter aerogenes ATCC 13048 > 100 100 > 100 Klebsiella pneumoniae ATCC 8045 > 100 100 > 100 Providencia struartii CMX 640 > 100 > 100 > 100 Pseudomonas aeruginosa BMH 10 > 100 100 > 100 Pseudomonas aeruginosa 5007 > 100 > 100 > 100 Pseudomonas aeruginosa K799 / WT 100 > 100 > 100 Pseudomonas aeruginosa K799 / 61 1.56 1.56 12.5 Pseudomonas capada 2961 > 100 > 100 > 100 Actinetobacter calcoaceficus CMX 669 12.5 12.5 25 Pseudomonas aeruginosa DPHD-5263 > 100 > 100 > 100 Pseudomonas aeruginosa DPHD-2862 > 100 > 100 > 100 Antibacterial Activity (MIC's) of Selected Compounds (Cont.)
Microorganisms Ery. A Example 7 Example 8 Candida albicans CCH 442 > 100 > 100 > 100 Mycobacteriun smegmatis ATCC 114 3.1 1.56 0.2 Staphylococcus aureus ATCC 6538 P 0.2 0.39 0.78 Staphylococcus aureus A5177 3.1 3.1 12.5 Staphylococcus aureus A-5278 > 100 > 100 > 100 Staphylococcus aureus CMX 642A 0.39 0.39 0.78 Staphylococcus aureus NCTC10649M 0.39 0.39 0.78 Staphylococcus aureus CMX 553 0.39 0.39 0.78 Staphylococcus aureus 1775 > 100 > 100 > 100 Staphylococcus epidermidis 3519 0.39 0.39 0.78 Enterococcus faecium ATCC 8043 0.05 0.39 0.39 Streptococcus bovis A-5169 0.02 0.01 0.2
Streptococcus agalactiae CMX 508 0.05 0.01 0.39 Streptococcus pyogenes EES61 - 0.01 0.1 Streptococcus pyogenes 93 > 100 > 100 > 100 Streptococcus pyogenes PIU 2548 3.1 - 25 Micrococcus luteus ATCC 9341 0.05 0.02 0.1 Micrococus luteus ATCC 4698 0.2 0.78 1.56 Escherichia coli JUHL > 100 12.5 100 Escherichia coli SS 0.78 0.2 1.56 Escherichia coli DC-2 > 100 6.2 > 100 Escherichia coli H560 50 1.56 50 Antibacterial Activity (MIC's) of Selected Compounds (Cont.)
Microorganisms Ery. A Example 7 Example 8
Escherichia coli KNK 437 100 12.5 > 100
Enterobacter aerogenes ATCC 13048 > 100 50 > 100 Klebsiella pneumoniae ATCC 8045 > 100 25 > 100
Providencia struartii CMX 640 > 100 > 100 > 100
Pseudomonas aeruginosa BMHIO > 100 25 > 100
Pseudomonas aeruginosa 5007 > 100 > 100 > 100
Pseudomonas aeruginosa K799 / WT 100 100 > 100 Pseudomonas aeruginosa K799 61 1.56 0.39 3.1
Pseudomonas capada 2961 > 100 > 100 > 100
Actitietobacte; - calcoaceticus CMX 669 12.5 12.5 50
Pseudomonas aeruginosa DPHD-5263 > 100 > 100 > 100
Pseudomonas aeruginosa DPHD-2862 > 100 > 100 > 100 Candida albicans CCH 442 > 100 > 100 > 100
Mycobacterium smegmatis ATCC 114 3.1 0.2 6.2 0.39
Table 2 Antibacterial Activity (MIC's) of Selected Compounds (Cont.)
Microorganisms Ery. A Exami2le 9 Example 10
Staphylococcus aereus ATCC 6538 P 0.2 3.1 0.2
Staphylococcus aureus A5177 3.1 - 6.2 Staphylococcus aureus A-5278 > 100 > 100 > 100 Staphylococcus aereus CMX 642a 0.39 3.1 0.39 Staphylococcus aureus NCTC10649M 0.39 3.1 0.39 Staphylococcus aureus CMX 553 0.39 - 0.39 Staphylococcus aureus 1775 > 100 > 100 > 100 Staphylococcus epidermidis 3519 0.39 3.1 0.2 Enterococcus faecium ATCC 8043 0.05 3.1 0.1 Streptococcus bovis A-5169 0.02 3.1 0.01 Streptococcus agalactiae CMX 508 0.05 3.1 0.05 Streptococcus pyogenes EES61 - - 0.01 Streptococcus pyogenes 930 > 100 > 100 > 100
Streptococcus pyogenes PIU 2548 3.1 12.5 -Micrococcus luteus ATCC 9341 0.05 3.1 0.05 Micrococcus luteus ATCC 4698 0.2 - 0.78 Escherichia coli JUHL > 100 > 100 50 Escherichia coli SS 0.78 - 0.78 Escherichia coli DC-2 > 100 - 100 Escherichia coli H560 50 > 100 25 Escherichia coli KNK 437 100 > 100 > 100 Enterobacter aerogenes ATCC 13048 > 100 > 100 > 100 Klebsiella pneumoniae ATCC 8045 > 100 > 100 > 100 Providencia struartii CMX 640 > 100 > 100 > 100 Pseudomonas aeruginosa BMHIO > 100 > 100 100 Pseudomonas aeruginosa 5007 > 100 > 100 > 100 Pseudomonas aeruginosa K799 / WT 100 > 100 > 100 Pseudomonas aeruginosa K799 / 61 1.56 12.5 3.1 Pseudomonas capada 2961 > 100 > 100 > 100 Actinotobacter calcoaceticus CMX 669 12.5 50 12.5 Pseudomonas aeruginosa DPHD-5263 > 100 > 100 > 100 Pseudomonas aeruginosa DPHD-2862 > 100 > 100 > 100 Candida albicans CCH 442 > 100 > 100 > 100 Mycobacterium smegmatis ATCC 114 3.1 3.1 0.39 Nocarrdia asteroids ATCC 9970
Table 2 Antibacterial Activity (MIC's) of Selected Compounds (Cont.)
Microorganisms Ery, A Example II Example 12 Staphylococcus aureus ATCC 6538P 0.2 0.78 0.39 Staphylococcus aureus A5177 3.1 6.2 -Staphylococcus aureus A-5278 > 100 > 100 > 100 Staphylococcus aureus CMX 642A 0.39 1.56 0.39 Staphylococcus aureus NCTC10649M 0.39 0.78 0.39 Staphylococcus aureus CMX 553 0.39 0.78 0.39 Staphylococcus aureus 1775 > 100 > 100 > 100 Staphylococcus epidermidis 3519 0.39 0.78 0.39 Enterococcus faecium ATCC 8043 0.05 0.39 0.1 Streptococcus bovis A-5169 0.02 0.2 0.05 Streptococcus agalactiae CMX 508 0.05 0.05 0.05 Streptococcus pyogenes EES61 - 0.05 0.05 Streptococcus pyogenes 930 > 100 > 100 > 100 Streptococcus pyogenes PIU 2548 3.1 25 12.5 Micrococcus luteus ATCC 9341 0.05 0.05 0.05 Micrococcus luteus ATCC 4698 0.2 - 0.78 Escherichia coli JUHL > 100 100 50 Escherichia coli SS 0.78 1.56 0.78 Escherichia coli DC-2 > 100 > 100 > 100 Escherichia coli H560 50 50 25 Escherichia coli KNK 437 100 > 100 100 Enterobacter aerogenes ATCC 13048 > 100 > 100 > 100 Klebsiella pneumoniae ATCC 8045 > 100 > 100 -Providencia struartii CMX 640 > 100 > 100 > 100 Pseudomonas aeruginosa BMHIO > 100 > 100 > 100 Pseudomonas aeruginosa 5007 > 100 > 100 > 100 Pseudomonas aeruginosa K799 / WT 100 > 100 > 100 Pseudomonas aeruginosa K799 / 61 1.56 - 1.56 Pseudomonas capada 2961 > 100 > 100 > 100 Actinetobacter calcoaceticus CMX 669 12.5 25 12.5 Pseudomonas aeruginosa DPHD-5263 > 100 > 100 > 100 Pseudomonas aeruginosa DPHD-2862 > 100 > 100 > 100 Candida albicans CCH 442 > 100 > 100 > 100
Mycobacteriun smegmatis ATCC II4 3.1 0.39 0.78 Nocarrdia asteroids ATCC 9970 0.1
It is understood that the foregoing detailed description and appended examples are merely illustrative and are not to be construed as limitations on the scope of the invention, which is defined only by the appended claims and their equivalents. Various changes and modifications to the modalities described will be apparent to those experts in the art, and can be done without departing from the spirit and scope of the same.
Claims (39)
1. A compound that has the formula: (ID; (III); (? V); (V); 071): (VII); (HIV); (DO; as well as the pharmaceutically acceptable salts, esters and pro-drugs thereof: wherein X is: (1) = O, (2) = N-OH, (3) = NO-R1 wherein R1 is (a) alkyl of unsubstituted C1-C12, (b) C1-C12 alkyl substituted with aryl, (c) substituted C? -C? 2 alkyl with substituted aryl, (d) C3-C12 cycloalkyl, (e) -Si- (R11) (R12) (R13) wherein R11, R12 and R13 are each independently selected from C1-C12 alkyl, (f) -Si- (arid) 3. or (4) = NOC (R9) (R10) -O-R1 wherein R1 is as defined above and R9 and R10 are independently selected from the group consisting of: (a) hydrogen, (b) C1 alkyl C12 unsubstituted, (c) C1-C12 alkyl substituted with aryl, (d) C1-C12 alkyl substituted with substituted aryl, or R9 and R10 taken together with the carbon to which they are attached form a cycloalkyl ring of C3- C12; Ra is hydrogen or hydroxy; Rb is hydrogen or hydroxy; one of Rc and Rd is hydrogen and the other of Rc and Rd is: (1) hydroxy, (2) protected hydroxy, (3) halogen, or (4) NR3R4 where R3 and R4 are independently selected from: (a) hydrogen, (b) C 1 -C 12 alkyl, (c) C 1 -C 12 alkyl substituted with aryl, (d) C 1 -C 12 alkyl substituted with substituted aryl, (e) C 1 -C 2 alkyl substituted with heteroaryl , and (f) substituted C 1 -C 12 alkyl with substituted heteroaryl, or (5) -SO 2 - (substituted dC 6 alkyl, or R 3 and R 4 taken together with the carbon to which they are attached form a 3-heterocycloalkyl ring. -7 members, or Rc and Rd taken together are: (1) = O, (2) = N-OH, (3) = N-OR where R1 is as defined above, Rβ is methoxy, fluoride or hydroxy; Rf is hydrogen or a hydroxy protecting group; R9 is selected from the group consisting of: (1) unsubstituted C?-C6 alkyl, (2) Ci-Cß alkyl substituted with one or more substituents selected from the group consisting of: (a) aryl, (b) ar substituted ilo, (c) heteroaryl, (d) substituted heteroaryl, (e) heteroarylalkyl, (f) hydroxy, (g) C? -C6 alkoxy, (h) NR3R4 wherein R3 and R4 are as defined above, and (i) -CH2-M-R5 wherein M is selected from a group consisting of: (i) -O-, (ii) -NH-, (iii) -NMe-, (iv) -S (O) n- where n is 0, 1 or 2, (v) -NHC (= O) -, and (vi) -C (= O) -NH-, and Rs is selected from a group consisting of: (j ) - (CH2) n-aryl where n is 0, 1 or 2, (vi) - (CH2) n-aryl substituted where n is 0, 1 or 2, (vii) - (CH2) p- heteroaryl wherein n = 0, 1 or 2, (viii) - (CH2) p-substituted heteroaryl wherein n is 0, 1 or 2, and (ix) - (CH2) p -heteroarylalkyl wherein n is 0.1 or 2, (3) C3-C cycloalkyl? ) (4) aryl, (5) substituted aryl, (6) heteroaryl, and (7) substituted heteroaryl; Rh is selected from the group consisting of: (a) hydrogen, (b) C 1 -C 12 alkyl, (c) C 1 -C 12 alkyl substituted with aryl, (d) C 1 -C 12 alkyl substituted with substituted aryl; (e) C 1 -C 12 alkyl substituted with heteroaryl, and (f) C 1 -C 12 alkyl substituted with substituted heteroaryl; R is selected from the group consisting of: (1) d-alkyl substituted with a substituent selected from the group consisting of: (a) F, (b) S (O) "R6 wherein n is 0, 1 or 2 and R 6 is C 1 Cs alkyl or C 1 -C 3 alkyl substituted with aryl, (c) NHC (O) R 6 wherein R 6 is as defined above, and (d) NHC (O) NR 3 R 4 wherein R 3 and R 4 are selected independently of hydrogen and C 1 -C 3 alkyl, (2) C -C 0 alkyl; (3) C2-C10 alkyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) ^ -C3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -C02R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 they are as previously defined, (i) = NO-R6 where R6 is as previously defined, (j) -C = N, (k) S (O) nR6 wherein n is 0, 1 or 2 and R6 is -CTS-C-alkyl or C1-C3-alkyl substituted with aryl, (I) aryl, ( m) substituted aryl, (n) heteroaryl, (o) substituted heteroaryl, (p) C3-C7 cycloalkyl, (q) (heteroaryl) alkyl, (r) NHC (O) R6 wherein R6 is as previously defined, (s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N-NR3R4 where R3 and R4 are as previously defined, (u) = N-NHC (O) R6 where R6 is as previously defined, and (v) = N-NHC (O) NR3R4 where R3 and R4 are as previously defined; (4) C 2 -C 0 alkenyl; (5) C2-C10 alkenyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C1-C3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -CO2R5 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 they are as previously defined, (i) = NO-R6 where R6 is as previously defined, (j) -C = N, (k) S (O) "R6 where n is 0, 1 or 2 and R6 is C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted with aryl, (I) aryl, (m) substituted aryl, (n) heteroaryl, (o) substituted heteroaryl, (p) C 3 -C 6 cycloalkyl, (q) (heteroaryl) alkyl, (r) NHC (O) R6 wherein R6 is as previously defined, (s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N-NR3R4 where R3 and R4 are as previously defined, (u) = N-NHC (O) R6 wherein R6 is as previously defined, and (v) = N-NHC (O) NR3R4 wherein R3 and R4 are as previously defined; (6) C2-C10 alkynyl; and (7) C -C10 Alkynyl substituted with one or more substituents selected from the group consisting of: (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) substituted heteroaryl; one of Y and Z is hydrogen and the other is selected from a group consisting of: (1) hydrogen, (2) hydroxy, (3) protected hydroxy, and (4) NR3R4 wherein R3 and R4 are as defined above; W is: (1) -O-, (2) -NH-, (3) -NMe-, or (4) absent; A, B, D and E are, in each occurrence, independently selected from the group consisting of: (1) hydrogen, (2) unsubstituted d-Ce alkyl, and (3) Ci-Cß alkyl substituted with one or more substituents selected from the group consisting of: (a) aryl, (b) substituted aryl, (c) heteroaryl, (d) substituted heteroaryl, (e) heteroarylalkyl, (f) hydroxy, (g) C? -C6 alkoxy , (h) NR3-R4, wherein R3 and R4 are as defined above, e (i) -CH2-M-R5 wherein M is selected from a group consisting of: (i) -O-, (ii) ) -NH-, (iii) -NMe-, (iv) -S (O) n- where n is 0, 1 or 2, (v) -NHC (= O) -, and (vi) -C ( = O) -NH-, and R5 is selected from a group consisting of: (i) - (CH2) n-aryl wherein n is 0, 1 or 2, (ii) - (CH2) n-aryl substituted on where n is 0, 1 or 2, (iii) - (CH2) n-heteroaryl wherein n = 0, 1 or 2, (vv) - (CH2) t.-substituted heteroaryl wherein n is 0, 1 or 2 , and (v) - (CH2) n-heteroarylalkyl wherein n is 0, 1 or 2, or any pair of substituents, with consisting of AB, AD, AE, BD, BE or DE, it is taken together with the atom or atoms to which they are attached to form a 3- to 7- membered ring optionally containing a hetero function selected from: (1) -O-, (2) -S (O) n-, where n is 0, 1 or 2, (3) -NH-, (4) -N (CH3) -, and (5) -N (R5 ) - where R5 is as previously defined.
2. A compound according to claim 1 having the formula: wherein X, R, Ra, Rb, Rc, Rd, Rβ and Rf are as defined herein.
3. A compound according to claim 1 having the formula: where Y, Z, R, Ra, Rb, Rc, Rd, Re and Rf are as defined herein.
4. A compound according to claim 1 having the formula: wherein R, Rb, Rc, Rd, Re and Rf are as defined herein.
5. A compound according to claim 1 having the formula: wherein R, R, R °, Ra, Re and Rr are as defined herein.
6. A compound according to claim 1 having the formula: wherein R, Ra, Rb, Rc, Rd, Rβ and Rf are as defined herein.
7. A compound according to claim 1 having the formula: wherein W, R, Rb, Rc, Rd, Re, Rf and Rs are as defined herein.
8. A compound according to claim 1 having the formula: where A, B, D, E, R, Rb, Rc, Rd, Re and Rf are as defined herein.
9. A compound according to claim 1 having the formula: where A, B, D, E, R, Rb, R °, Rd, Re, Rf and Rh are as defined herein.
10. A compound according to claim 2 wherein Ra is hydroxy, Rfa is hydrogen, Rc is hydrogen, Rd is hydroxy, Rβ is methoxy, and Rf is hydrogen.
11. A compound according to claim 3 wherein Ra is hydroxy, Rb is hydrogen, Rc is hydrogen, Rd is hydroxy, Rβ is methoxy, and Rf is hydrogen.
12. A compound according to claim 1 which is selected from the group consisting of: Compound of Formula (X): X is = N-O- (1-isopropoxycyclohexyl), R is allyl; Compound of Formula (X): X is = O, R is allyl; Compound of Formula (X): X is = O, R is propyl; Compound of Formula (X): X is = O, R is 2,3-dihydroxypropyl; Compound of Formula (X): X is = O, R is 2,3-epoxypropyl; Compound of Formula (X): X is = O, R is 2-hydroxy-3- (imidazol-1-yl) propyl; Compound of Formula (X): X is = O, R is 2-hydroxy-3- (morpholin-4-yl) propyl; Compound of Formula (X): X is = O, R is 2-hydroxy-3- (benzylamine) propyl; Compound of Formula (X): X is = O, R is 2-oxoethyl; Compound of Formula (X): X is = O, R is 2-oxopropyl; Compound of Formula (X): X is = O, R is -CH2-C = CH; Compound of Formula (X): X is = O, R is -CH2-CHOH-CH2-N3; Compound of Formula (X): X is = O, R is -CH2-CH = N-OH; Compound of Formula (X): X is = O, R is -CH 2 -CH 2 OH; Compound of Formula (X): X is = O, R is -CH2-CH2NH2; Compound of Formula (X): X is = O, R is -CH2-CN; Compound of Formula (X): X 6s = O, R is -CH 2-Phenyl; Compound of Formula (X): X is = O, R is -CH2-CH = CH (Phenyl); Compound of Formula (X): X is = O, R is -CH2-CH = N-0-CH3; Compound of Formula (X): X is = O, R is -CH2-CH = N-O-CH2-Phenyl; Compound of Formula (X): X is = O, R is -CH2-CH = N-N (CH3) 2; Compound of Formula (X): X is = O, R is -CH2-CH = N-NH (CH3); Compound of Formula (X): X is = O, R is -CH 2 -CH = N- (4-Morpholinyl); Compound of Formula (X): X is = O, R is -CH 2 -CH = N-NH (Phenyl); Y Compound of Formula (X): X is = O, R is -CH2-CH = N-N (Phenyl) 2; Compound of formula (X): X is = = O, R is -CH2CH2CH20H; Compound of the formula (X): X is = = 0, R is -CH2-C02H, Compound of the formula (X): X is = = O, R is -CH2CH2N H (CH3); Compound of formula (X): X is = = O, R is -CH2CH2NHCH2CH3; Compound of the formula (X): X is = = O, R is -CH2CH2N HCH2CH2-Phenyl; Compound of the formula (X): X is = = O, R is -CH2CH2N (CH3) 2; Compound of formula (X): X is = = O, R is -CH2CH2- (4-morpholinyl); Compound of the formula (X): X is = = O, R is -CH2C (O) NH2; Compound of the formula (X): X is = = O, R is -CH2NHC (O) NH2; Compound of the formula (X): X is = = O, R is -CH2NHC (O) CH3; Compound of the formula (X): X is = = O, R is -CH2F; Compound of the formula (X): X is = = O, R is -CH2CH2OCH3; Compound of the formula (X): X is = = O, R is -CH2CH3; Compound of the formula (X): X is = = 0, R is -CH2CH = C (CH3) 23; Compound of the formula X): X is = O, R is -CH2CH = CHF; Compound of the formula X): X is = O, R is - (CH2) 3-F; Compound of formula X): X is = O, R is - (CH 2) 2 -CH (CH 3) 2; Compound of the formula X): X is = O, R is - (CH2) 2-O- (CH2) 2-O-CH3; Compound of formula X): X is = O, R is -CH2-F; Compound of the formula X): X is = N-OH, R is -CH2-C = CH; Compound of formula X): X is = N-O-CH3, R is -CH2-C = CH; Compound of formula X): X is = N-O-Benzyl, R is -CHz-C = CH; Compound of the formula X): X is = N-O-CH2-O-CH3, R is -CH2-C = CH; Compound of formula X): X is = N-O-CH2-O-CH2-CH2-O-CH3, R is -Composed of formula X): X is = N-OH, R is -CH2-CH = CH2; Compound of the formula X): X is = N-O-CH3, R is -CH2-CH = CH2; Compound of the formula X): X is = N-O-Benzyl, R is -CH 2 -CH = CH 2; Compound of formula X): X is = N-O-CH2-O-CH3, -CH2-CH = CH2; Compound of formula X): X is = N-O-CH2-O-CH2-CH2-O-CH3, R is CH2-CH = CH2; Compound of formula XI): Y is NH2, Z is H, R is -CH2-C = CH; Compound of formula XI): Y is NH-CH2CH2CH3, Z is H, R is -CH2 C = CH; Compound of the formula (XI): Y is NH- (CH2) 9-CH3, Z is H, R is -CH2- C = CH; Compound of formula (XI): Y is NH-CH (CH3) 2, Z is H, R is -CH2-C = CH; Compound of the formula (XI): Y is I -piperidinyl, Z is H, R is -CH2-C = CH; Compound of formula (XI): Y is H, Z is I -piperidinyl, R is -CH2-C = CH; Compound of Formula (XI): Y is H, Z is NH2, R is CH2-C = CH; Compound of Formula (XI): Y is H, Z is NH-CH2CH2CH3, R is -CH2- C = CH; Compound of Formula (XI): Y is H, Z is NH-CH2CH2CH3, R is -CH2- C --- CH; Compound of Formula (XI): Y is H, Z is NH-CH (CH3) 2, R is -CH2- Compound of Formula (XI): Y is OH, Z is H, R is -CH2-C- = CH; Compound of Formula (XI): Y is H, Z is OH, R is -CH2-C --- CH; Compound of Formula (IV): R is -CH2CH = CH2, Rb is H, Rc is H, Rd is OH, Re is OCH3, Rf is hydrogen; Compound of Formula (IV): R is -CH2-C = CH, Rb is H, Rc is H, Rd is OH, Re is OCH3, Rf is hydrogen; Compound of Formula (IV): R is -CH2-C- = N, R is H, Rc is H, Rd is OH, Re is OCH3, Rf is hydrogen; Compound of Formula (V): R is -CH2CH = CH2, Rb is H, Rc is H, Rd is OH, Rβ is OCH3, Rf is hydrogen; Compound of Formula (V): R is -CH2-C = CH, Rb is H, Rc is H, Rd is OH, Re is OCH3, Rf is hydrogen; Compound of Formula (V): R is -CH2-C = N, Rb is H, Rc is H, Rd is OH, Rβ is OCH3, Rf is hydrogen; Compound of Formula (VI): R is -CH2CH = CH2, Ra is OH, Rb is H, Rc is H, Rd is OH, Re is OCH3, Rf is hydrogen; Compound of Formula (VI): R is -CH2-C = CH, Ra is OH, R is H, Rc is H, Rd is OH, Re is OCH3, Rf is hydrogen; Compound of Formula (VI): R is -CH2-C = N, Ra is OH, Rb is H, Rc is H, Rd is OH, Re is OCH3, Rf is hydrogen; Compound of the Formula (VII): R is -CH2CH = CH2 and W, R, Rc, Rd, Re, Rf and R8 are as previously defined; Compound of the Formula (VII): R is -CH2-C = CH and W, Rb, Rc, Rd, Re, Rf and R9 are as previously defined; Compound of the Formula (VII): R is -CH2-C --- N and w, Rb, Rc, Rd, Rβ, Rf and R9 are as previously defined; Compound of Formula (VIII): R is -CH2-CH = CH2 and A, B, D, E, Rb, R °, Rd, Rβ and Rf are as previously defined; Compound of Formula (VIII): R is -CH2-C- = CH and A, B, D, E, Rb, Rc, Rd, Re and Rf are as previously defined; Compound of Formula (VIII): R is -CH2-C = N and A, B, D, E, Rb, Rc, Rd, Re and Rf are as previously defined; Compound of the formula (IX): R is -CH2CH = CH2, and A, B, D, E, R, Rc, Rd, Re, Rf and Rh are as previously defined; Compound of the formula (IX): R is -CH2-C = CH, and A, B, D, E, Rb, Rc, Rd, Rβ, Rf and Rh are as previously defined; Compound of the formula (IX): R is -CH2-C = N, and A, B, D, E, Rb, Rc, R, Re, Rf and Rh are as previously defined; Compound of Formula (II): X is = O, R is -CH2CH = CH2, Rc and Rd taken together are = O, and Ra, Rb, Re and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C- = CH, Rc and Rd taken together are = O, and Ra, Rb, Re and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C = N, Rc and Rd taken together are = O, and Ra, Rb, Re and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2CH = CH2, Rc is -OH, Rd is -H, Re is -OCH3; and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C = CH, Rc is -OH, Rd is -H, Rβ is -OCH3; and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C = N, Rc is -OH, Rd is -H, Re is -.OCH3; and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2CH = CH2, Rc is -N (CH3) 2, Rd is -H, Rβ is -OCH3 and Ra, Rb Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH -C = CH, R ° is -N (CH3) 2, Rd is -H, Re is -OCH3 and Ra, Rb, and Rf are as were previously defined; Compound of Formula (II): X is = O, R is -CH2-C = N, Rc is -N (CH3) 2, Rd is -H, Re is -OCH3 and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2CH = CH2, Rc is -H, Rd is -N (CH3) 2, Re is -OCH3 and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C = CH, Rc is -H, Rd is -N (CH3) 2, Re is -OCH3 and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C = N, R ° is -H, Rd is -N (CH3) 2, R? is -OCH3 and Ra, Rb, and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2CH = CH2, Rc is -H, Rd is -OCH3, Rc is -F and Ra, Rb and Rf are as previously defined; Compound of Formula (II): X is = O, R is -CH2-C = CH, Rc is -H, Rd is -OCH3, Re is -F and Ra, Rb and Rf are as previously defined; and Compound of Formula (II): X is = O, R is -CH2-C = N, Rc is -H, Rd is -OCH3, Rc is -F and Ra, R and Rf are as previously defined; as well as the pharmaceutically acceptable salts, esters and pro-drugs thereof.
13. A compound according to claim 2 which is selected from the group consisting of: Compound of the Formula (X): X is = N-O- (1-isopropoxycyclohexyl), R is allyl; Compound of Formula (X): X is = O, R is allyl; Compound of Formula (X): X is = O, R is propyl; Compound of Formula (X): X is = O, R is 2,3-dihydroxypropyl; Compound of Formula (X): X is = O, R is 2,3-epoxypropyl; Compound of Formula (X): X is = O, R is 2-hydroxy-3- (imidazol-1-yl) propyl; Compound of Formula (X): X is = O, R is 2-hydroxy-3- (morpholin-4-yl) propyl; Compound of Formula (X): X is = O, R is 2-hydroxy-3- (benzylamine) propyl; Compound of Formula (X): X is = O, R is 2-oxoethyl; Compound of Formula (X): X is = O, R is 2-oxopropyl; Compound of Formula (X): X is = O, R is -CH2-C --- CH; Compound of Formula (X): X is = O, R is -CH2-CHOH-CH2-N3; Compound of Formula (X): X is = O, R is -CH2-CH = N-OH; Compound of Formula (X): X is = O, R is -CH 2 -CH 2 OH; Compound of Formula (X): X is = O, R is -CH2-CH2NH2; Compound of Formula (X): X is = O, R is -CH2-CN; Compound of Formula (X): X is = O, R is -CH2-Phenyl; Compound of Formula (X): X is = O, R is -CH2-CH = CH (Phenyl); Compound of Formula (X): X is = O, R is -CH2-CH = N-0-CH3; Compound of Formula (X): X is = O, R is -CH2-CH = N-O-CH2-Phenyl; Compound of Formula (X): X is = O, R is -CH2-CH = N-N (CH3) 2; Compound of Formula (X): X is = O, R is -CH2-CH = N-NH (CH3); Compound of Formula (X): X is = O, R is -CH 2 -CH = N- (4-Morpholinyl); Compound of Formula (X): X is = O, R is -CH 2 -CH = N-NH (Phenyl); Y Compound of Formula (X): X is = O, R is -CH2-CH = N-N (Phenyl) 2; as well as the pharmaceutically acceptable salts, esters and pro-drugs thereof.
14. A compound according to claim 2 which is selected from the group consisting of: Compound of Formula (X): X is = O, R is allyl, Rb is CH3; Compound of Formula (X): X is = O, R is 2-hydroxy-3-propyl (benzylamine), R is CH3; Compound of Formula (X): X is = O, R is 2-oxopropyl, Rb is CH3; Compound of Formula (X): X is = O, R is -CH2-C = CH, Rb is CH3; Compound of Formula (X): X is = O, R is -CH2-CH = N-OH, Rb is CH3; Compound of Formula (X): X is = O, R is -CH2-CH2OH, Rb is CH3; Compound of Formula (X): X is = 0, R is -CH2-CH2N H2; and Compound of Formula (X): X is = O, R is -CH2-CN; as well as the pharmaceutically acceptable salts, esters and pro-drugs thereof.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
16. A method for controlling a bacterial infection in a mammal comprising administering to an animal a therapeutically effective pharmaceutical composition containing a compound according to claim 1.
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 2. in combination with a pharmaceutically acceptable carrier.
18. A method for controlling a bacterial infection in a mammal comprising administering to an animal a therapeutically effective pharmaceutical composition containing a compound according to claim 2.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. claim 3 in combination with a pharmaceutically acceptable carrier.
A method for controlling a bacterial infection in a mammal comprising administering to an animal a therapeutically effective pharmaceutical composition containing a compound according to claim 3.
21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. claim 4 in combination with a pharmaceutically acceptable carrier.
22. A method for controlling a bacterial infection in a mammal comprising administering to an animal a therapeutically effective pharmaceutical composition containing a compound according to claim 4.
23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 5 in combination with a pharmaceutically acceptable carrier.
24. A method for controlling a bacterial infection in a mammal comprising administering to an animal a therapeutically effective pharmaceutical composition containing a compound according to claim 5.
25. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. claim 6 in combination with a pharmaceutically acceptable carrier.
26. A method for controlling a bacterial infection in a mammal comprising administering to an animal a therapeutically effective pharmaceutical composition containing a compound according to claim 6.
27. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. claim 7 in combination with a pharmaceutically acceptable carrier.
28. A method for controlling a bacterial infection in a mammal comprising administering to an animal a therapeutically effective pharmaceutical composition containing a compound according to claim 7.
29. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 8 in combination with a pharmaceutically acceptable carrier.
30. A method for controlling a bacterial infection in a mammal comprising administering to an animal a therapeutically effective pharmaceutical composition containing a compound according to claim 8.
31. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. claim 9 in combination with a pharmaceutically acceptable carrier.
32. A method for controlling a bacterial infection in a mammal comprising administering to an animal a therapeutically effective pharmaceutical composition containing a compound according to claim 9.
33. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. claim 13 in combination with a pharmaceutically acceptable carrier.
34. A method for controlling a bacterial infection in a mammal comprising administering to an animal a therapeutically effective pharmaceutical composition containing a compound according to claim 13.
35. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention. claim 14 in combination with a pharmaceutically acceptable carrier.
36. A method for controlling a bacterial infection in a mammal comprising administering to an animal a therapeutically effective pharmaceutical composition containing a compound according to claim 14.
37. A process for the preparation of substituted macrolide compounds in 6-O- that have ls formulas: 01); (10); OVD; (VII); (Vm); (ix); of x is: (1) = O, (2) = N-OH, (3) = NO-R1 wherein R1 is (a) unsubstituted C? -C12 alkyl, (b) C? -C alkyl 2 substituted with aryl, (c) substituted C 1 -C 2 alkyl with substituted aryl, (d) C3-C2 cycloalkyl, (e) -Si- (R11) (R1) (R13) wherein R11, R12 and R13 are each independently selected from alkyl of (f) -Si- ( aryl) 3, or (4) = NOC (R9) (R10) -O-R1 wherein R1 is as defined above and R9 and R10 are independently selected each from the group consisting of: (a) hydrogen, (b) unsubstituted C 1 -C 12 alkyl, (c) C 1 -C 12 alkyl substituted with aryl, (d) C 1 -C 12 alkyl substituted with substituted aryl, or R 9 and R 10 taken together with the carbon to which they are bound form a cycloalkyl ring of C3-C? 2; Ra is hydrogen or hydroxy; Rb is hydrogen or hydroxy; one of Rc and Rd is hydrogen and the other of Rc and Rd is: (1) hydroxy, (2) protected hydroxy, (3) halogen, or (4) NR3R4 where R3 and R4 are independently selected from: (a) hydrogen, (b) dC? 2 alkyl, (c) substituted C? -C? 2 alkyl with aryl, (d) substituted dC? 2 alkyl with substituted aryl, (e) substituted C? -C12 alkyl with heteroaryl, and (f) C 1 -C 12 alkyl substituted with substituted heteroaryl, or (5) -SO 2 - (substituted C 1 -C 4 alkyl, or R 3 and R 4 taken together with the carbon to which they are attached form a heterocycloalkyl ring of 3-7 members, or Rc and Rd taken together are: (1) = O, (2) = N-OH, (3) = N-OR1 where R1 is as defined above, Re is methoxy, fluorine or hydroxy; Rf is hydrogen or a hydroxy protecting group: Rs is selected from the group consisting of: (1) unsubstituted C? -C6 alkyl, (2) substituted C? -C6 alkyl with one or more substituents selected from the group consists of: (a) aryl, (b) aryl s ubstituted, (c) heteroaryl, (d) substituted heteroaryl, (e) heteroarylalkyl, (f) hydroxy, (g) C? -C6 alkoxy, (h) NR3R4 wherein R3 and R4 are as defined above, and ( i) -CH2-M-RS wherein M is selected from a group consisting of: (> ) -O-, (Ü) -NH-, (iii) -NMe-, (iv) -S (O) "- where n is 0, 1 or 2, (v) -NHC (= O) -, and (vi) -C (= O) -NH-, and Rs is selected from a group consisting of: (i) - (CH2) p-aryl wherein n is 0, 1 or 2, (ii) - ( CH2) "- substituted aryl wherein n is 0, 1 or 2, (iii) - (CH2) p -heteroaryl wherein n = 0, 1 or 2, (iv) - (CH2) n -substituted heteroaryl wherein n is 0, 1 or 2, and (v) - (CH2) n-heteroarylalkyl wherein n is 0, 1 or 2, (3) C3-C12 cycloalkyl, (4) aryl, (5) substituted aryl, (6) heteroaryl, and (7) substituted heteroaryl; Rh is selected from the group consisting of: (a) hydrogen, (b) C 1 -C 2 alkyl, (c) C 1 -C 2 alkyl substituted with aryl, (d) C 1 -C alkyl 2 substituted with substituted aryl; (e) C 1 -C 2 alkyl substituted with heteroaryl, and (f) C 1 -C 2 alkyl substituted with substituted heteroaryl; R is selected from the group consisting of: (1) d-alkyl substituted with a substituent selected from the group consisting of: (a) F, (b) S (O) nR6 wherein n is 0, 1 or 2 and R6 is C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted with aryl, (c) NHC (O) R 6 wherein R 6 is as defined above, and (d) NHC (O) NR 3 R 4 wherein R 3 and R 4 are selected independently of hydrogen and C 1 -C 3 alkyl, (2) C 2 -C 10 alkyl; (3) C 2 -C 0 alkyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C 1 -C 3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -C02R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 are as previously defined, (i) = NO-R6 where R6 is as previously defined, (j) -C- ^ N, (k) S (O) pR6 where n is 0, 1 or 2 and R6 is d-C3 alkyl or C1-C3 alkyl substituted with aryl, (I) aryl, (m) substituted aryl, (n) heteroaryl, (o) substituted heteroaryl, (p) C3-C7 cycloalkyl, (q) (heteroaryl) alkyl, (r) NHC (O) R6 wherein R6 is as previously defined, (s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N- NR3R4 wherein R3 and R4 are as previously defined, (u) = N-NHC (O) R6 where R6 is as previously defined, and (v) = N-NHC (O) NR3R4 where R3 and R4 are as defined n previously; (4) C 2 -C 0 alkenyl; (5) C2-C10 alkenyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C? -C3 alkoxy, (d) oxo (C = O) , (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 are as previously defined, (i) = NO-R6 where R6 is as previously defined, (j) -C = N, (k) S (O) "R6 where n is 0, 1 or 2 and R6 is C?-C3 alkyl or aryl-substituted d-C3 alkyl, (I) aryl, (m) substituted aryl, (n) heteroaryl, (o) substituted heterobaryl, (p) C3-C7 cycloalkyl, ( q) (heteroaryl) alkyl, (r) NHC (O) R6 wherein R6 is as previously defined, (s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N-NR3R4 where R3 and R4 are as previously defined, (u) = N-NHC (O) R6 wherein R6 is as previously defined, and (v) = N-NHC (O) NR3R4 wherein R3 and R4 are as previously defined; (6) Alkynyl of C2-C? 0; and (7) C2-C alkynyl or substituted with one or more substituents selected from the group consisting of: (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) heteroaryl replaced; one of Y and Z is hydrogen and the other is selected from a group consisting of: (1) hydrogen, (2) hydroxy, (3) protected hydroxy, and (4) NR3R4 wherein R3 and R4 are as defined above; W is: (1) -O-, (2) -NH-, (3) -NMe-, or (4) absent; A, B, D and E are, in each occurrence, independently selected from the group consisting of: (1) hydrogen, (2) unsubstituted d-C6 alkyl, and (3) substituted C? -C6 alkyl with one or more substituents selected from the group consisting of: (a) aryl, (b) substituted aryl, (c) heteroaryl, (d) substituted heteroaryl, (e) heteroarylalkyl, (f) hydroxy, (g) C 1 alkoxy Ce, (h) NR3-R4, wherein R3 and R4 are as defined above, e (i) -CH2-M-R5 wherein M is selected from a group consisting of: (i) -O-, ( ii) -NH-, (iii) -NMe-, (iv) -S (O) n- where n is 0, 1 or 2, (v) -NHC (= O) -, and R5 is selected from a group consisting of: (i) - (CH2) n-aryl where n is 0, 1 or 2, (ii) - (CH2) n-aryl substituted where n is 0, 1 or 2, (iii) - (CH2) n-heteroaryl wherein n = 0, 1 or 2, (iv) - (CH2) n -substituted heteroaryl wherein n is 0, 1 or 2, and (v) - (CH2) n-heteroarylalkyl wherein n is 0, 1 or 2, or any pair of substituents, consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7- membered ring optionally containing a hetero function selected from: (D -o-, (2) -S (O) p-, where n is 0, 1 or 2, (3) -NH-, (4) -N (CH3) -, and (5) -N (R5) - where R5 is as defined previously, it is a method comprising: (a) treating a compound having the formula: wherein R is a hydroxy protecting group and V is = NO-R1 or = NOC (R9) (R10) -O-R1 wherein R1, R9 and R10 are as defined above, with a base, such as hydroxide potassium, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potassium tert-butoxide, potassium isobutoxide, in an aprotic solvent, as defined below, which does not adversely affect the reaction, preferably dimethylsulfoxide, diethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone, with cooling or heating, depending on the conditions used, at a temperature of about -15 ° C to about 50 ° C, for a period of 0.5 hours to 10 days, preferably 1-5 days, with an alkylating agent such as or allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, a-bromo-p-tolunitrile, cinnamyl bromide, 4 -methyl bromoprotate, crotyl bromide, 1-bromo-2-pentene, 3-bromo-1 -propenyl phenyl sulfone, 3-bromo-1-trimethylsilyl-1-propynyl, 3-bromo-2-octyne, 1-bromine -2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromomethyl quinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bromochloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-1-propene, allyl-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate, or n-butyl-O-methanesulfonate; to give a compound that has the formula: where A, B, D, E, W, X, Y, Z, Ra, Rb, Rc, Rd, Re, Rf, R9, and Rh are as defined above, V is = NO-R1 or = NOC ( R9) (R10) -O-R1 wherein R1, R9 and R10 are as defined above, and R is the "alkyl group" derived from the corresponding alkylating agent; (b) deprotecting the hydroxyl groups in 2'- and 4'-, for example, using acetic acid in water and acetonitrile to give a compound of the formula: ; or wherein A, B, D, E, W, X, Y, Z, Ra, Rb, Rc, Rd, Rβ, Rf, R9 and Rh are as defined above and R is the "alkyl group" derived from the agent corresponding alkylator; and (c) deoximation using, for example, inorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, dithionate of sodium, potassium thiosulfate, or potassium metabisulfite in a solvent such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol or a mixture of one or more of the mentioned solvents to give the desired products.
38. The process according to claim 37 for the preparation of 6-O- substituted macrolide compounds having the formula: of X is: (1) = O, (2) = N-OH, (3) = NO-R1 wherein R1 is: (a) unsubstituted C? -C? 2 alkyl, (b) C-alkyl ? -C? 2 substituted with aryl, (c) substituted C? -C? 2 alkyl with substituted aryl, (d) C3-C? 2 cycloalkyl, (e) -Si- (R1 1) (R12) ( R13) wherein R11, R12 and R13 are each independently selected from C? -C12 alkyl, (f) -Si- (aryl) 3, or (4) = NOC (R9) (R10) -O-R1 wherein R1 is as defined above and R9 and R10 are independently selected from the group consisting of: (a) hydrogen, (b) unsubstituted C? -C? 2 alkyl, (c) C? -C12 alkyl substituted with aryl, (d) substituted d-C12 alkyl with substituted aryl, or R9 and R10 taken together with the carbon to which they are bound they form a cycloalkyl ring of C3-C? 2; R is selected from the group consisting of: (1) Ci alkyl substituted with a substituent selected from the group consisting of: (a) F, (b) S (O) "R6 wherein n is 0, 1 or 2 and R6 is C? -C3 alkyl or C? -C3 alkyl substituted with aryl, (c) NHC (O) R6 wherein R6 is as defined above, and (d) NHC (O) NR3R4 wherein R3 and R4 are independently selected from hydrogen and C? -C3 alkyl, (2) C2-C? alkyl; (3) C 2 -C 0 alkyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C 1 -C 3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 are as previously defined, (i) = NO-R6 where R6 is as previously defined, (j) -C- = N, (k) S (O) nR6 where n is 0, 1 or 2 and R6 is C?-C3 alkyl or d-C3 alkyl substituted with aryl, (I) aryl, (m) substituted aryl, (n) heteroaryl, (o) substituted heteroaryl, (p) C3-C7 cycloalkyl , (q) (heteroaryl) alkyl, (r) NHC (O) R6 wherein R6 is as previously defined, (s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N -NR3R4 wherein R3 and R4 are as previously defined, (u) = N-NHC (O) R6 where R6 is as previously defined, and (v) = N-NHC (O) NR3R4 where R3 and R4 they are as defined previously; (4) C2-C10 alkenyl; (5) C2-C al alkenyl or substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C?-C3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 are as previously defined, (i) = NO-R6 where R6 is as previously defined, (j) -CN, (k) S (O) nR6 where n is 0, 1 or 2 and R6 is C?-C3 alkyl or alkyl of C? -C3 substituted with aryl, (I) ary, (m) substituted aryl, (n) heteroaryl, (o) susbtituido heteroaryl, (p) C3-C7 cycloalkyl, (q) (heteroaryl) alkyl, (r) ) NHC (O) R6 where R6 is as previously defined, (s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N-NR3R4 where R3 and R4 are as previously defined, (u) = N-NHC (O) R6 where R6 is as previously defined, and (v) = N-NHC (O) NR3R4 wherein R3 and R4 are as previously defined; (6) Alkynyl of C2-C? 0; and (7) C2-C Al alkynyl or substituted with one or more substituents selected from the group consisting of: (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) heteroaryl replaced; it is a method that comprises: (a) treating a compound that has the formulas: wherein Rp is a hydroxy protecting group and V is = NO-R1 or = NOC (R9) (R10) -O-R1 wherein R1, R9 and R10 are as defined above, with a base, such as hydroxide potassium, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potassium tert-butoxide, potassium isobutoxide, in an aprotic solvent, as defined below, which does not adversely affect the reaction, preferably dimethylsulfoxide, diethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone, with cooling or heating, depending on the conditions used, at a temperature of about -15 ° C to about 50 ° C, for a period of 0.5 hours to 10 days, preferably 1-5 days, with an alkylating agent such such as allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, α-bromo-p-tolunitrile, cinnamyl bromide, 4 -methyl bromoprotate, crotyl bromide, 1-bromo-2-pentene, 3-bromo-1-propenyl phenyl suifone, 3-bromo-1-trimethylsilyl-1-propynyl, 3-bromo-2-octyne, 1-bromo -2-butyne, 2-picolyl chloride, 3-picoyl chloride, 4-picoyl chloride, 4-bromomethyl quinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bromochloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-1-propene, allyl-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate, or n-butyl-O-methanesulfonate; to give a compound that has the formula: wherein V and Rp are as defined above and R is the "alkyl group" derived from the corresponding alkylating agent; (b) deprotecting the hydroxyl groups in 2'- and 4'-, for example, using acetic acid in water and acetonitrile to give a compound having the formula: (c) deoximation, for example, using inorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate , potassium thiosulfate, or potassium metabisulfite in a solvent such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol, or a mixture of one or more of the aforementioned solvents.
39. The process according to claim 38 for the preparation of 6-O- substituted macrolide compounds having the formula: wherein X is: (1) = O, (2) = N-OH, (3) = NO-R1 wherein R is (a) unsubstituted C? -C12 alkyl, (b) C? C? 2 substituted with aryl, (c) substituted C? -C? 2 alkyl with substituted aryl, (d) C3-C7 cycloalkyl, (e) -Si- (R1 1) (R12) (R13) wherein R1 1, R12 and R13 are each independently selected from d-C12 alkyls, (f) -Si- (halo) 3, or (4) = NOC (R9) (R10) -O-R1 wherein R1 is as defined above and R9 and R10 are each independently selected from the group consisting of: (a) hydrogen, (b) unsubstituted C? -C? 2 alkyl, (c) dC? 2 alkyl substituted with aryl , and (d) substituted C 1 -C 2 alkyl with substituted aryl, or R 9 and R 10 taken together with the carbon to which they are attached form a cycloalkyl ring of C 3 -C 2; and R is selected from the group consisting of: (1) d-alkyl substituted with a substituent selected from the group consisting of: (a) F, (b) S (O) nR6 wherein n is 0, 1 or 2 and alkyl of d-C3 or alkyl of C? -C3 substituted with aryl, (c) NHC (O) R6 wherein R6 is as defined above, and (d) NHC (O) NR3R4 where R3 and R4 are independently selected of hydrogen and C3-alkyl, (2) C2-C10 alkyl; (3) C 2 -C 0 alkyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C? -C3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) - C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 are as previously defined, (i) = NO-R6 where R6 is as previously defined, (j) ) -C = N, (k) S (O) "Rd where n is 0, 1 or 2 and R6 is C?-C3 alkyl or C?-C3 alkyl substituted with aryl, (I) aryl, ( m) substituted aryl, (n) heteroaryl, (o) substituted heteroaryl, (p) C3-C7 cycloalkyl, (q) (heteroaryl) alkyl, (r) NHC (O) R6 wherein R6 is as previously defined, (s) NHC (0) N R3R4 wherein R3 and R4 are as previously defined, (t) = N-NR3R4 where R3 and R4 are as previously defined, (u) = N-NHC (O) R6 in where R6 is as previously defined, and (v) = N-NHC (O) NR3R4 where R3 and R4 are as previously defined; (4) C2-C10 alkenyl; (5) C 2 -C 0 alkenyl substituted with one or more substituents selected from the group consisting of: (a) halogen, (b) hydroxy, (c) C 1 -C 3 alkoxy, (d) oxo (C = O), (e) -CHO, (f) -CO2R6 wherein R6 is as defined above, (g) -C (O) NR3R4 wherein R3 and R4 are as previously defined, (h) -NR3R4 wherein R3 and R4 are as previously defined, (i) = NO-R6 where R6 is as previously defined, (j) -C = N, (k) S (O) pR6 wherein n is 0, 1 or 2 and R6 is d-C3 alkyl or C?-C3 alkyl substituted with aryl, (I) aryl, ( m) substituted aryl, (n) heteroaryl, (o) susbtituido heteroaryl, (p) C3-C7 cycloalkyl, (q) (heteroaryl) alkyl, (r) NHC (O) R6 wherein R6 is as previously defined, (s) NHC (O) NR3R4 wherein R3 and R4 are as previously defined, (t) = N-NR3R4 where R3 and R4 are as previously defined, (u) = N-NHC (O) R6 where R6 is as previously defined, and (v) = N-NHC (O) N R3R4 wherein R3 and R4 are as previously defined; (6) C 2 -C 8 Alkynyl; and (7) C2-C alkynyl or substituted with one or more substituents selected from the group consisting of: (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) heteroaryl replaced; is a method comprising: (a) treating a compound having the formula: wherein Rp is trimethylsilyl and V is O- (l-isopropoxycyclohexyl) oxime with potassium hydroxide in a mixture of THF and DMSO with an alkylating agent such as allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, a-bromo-p-tolunitrile, cinnamyl bromide, 4- methyl bromocronate, crotyl bromide, 1-bromo-2-pentene: 3-bromo-1-propenyl phenyl sulfone, 3-bromo-1-trimethylsilyl-1-propino, 3-bromo-2-octino, 1-bromo- 2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromomethyl quinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, -bromo-2-butanone, bromochloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-1-propene, allyl-tosylate, 3-phenylpropyl-Ot rifluoromethane sulfonate, or n-butyl-O-methanesulfonate; to give a compound that has the formula: wherein V and Rp are as defined above and R is the "alkyl group" derived from the corresponding alkylating agent; (b) deprotecting the hydroxyl groups in 2'- and 4'- using acetic acid in water and acetonitrile to give a compound having the formula: ; and (c) deoximating the 9-oxime using NaHSO3 and formic acid in ethanol-water to give the desired product.
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US646477 | 1996-05-07 |
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