OA17212A - Macrolide derivatives, preparation thereof and therapeutic use thereof. - Google Patents
Macrolide derivatives, preparation thereof and therapeutic use thereof. Download PDFInfo
- Publication number
- OA17212A OA17212A OA1201500093 OA17212A OA 17212 A OA17212 A OA 17212A OA 1201500093 OA1201500093 OA 1201500093 OA 17212 A OA17212 A OA 17212A
- Authority
- OA
- OAPI
- Prior art keywords
- group
- oxy
- pyran
- hydroxy
- methyltetrahydro
- Prior art date
Links
- 230000001225 therapeutic Effects 0.000 title abstract description 8
- 239000003120 macrolide antibiotic agent Substances 0.000 title description 6
- 238000002360 preparation method Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 328
- 238000004519 manufacturing process Methods 0.000 claims abstract 5
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 292
- -1 3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-ylmethyl Chemical group 0.000 claims description 125
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 claims description 77
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 37
- 201000008827 tuberculosis Diseases 0.000 claims description 37
- 125000001072 heteroaryl group Chemical group 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 238000007792 addition Methods 0.000 claims description 28
- 125000004076 pyridyl group Chemical group 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 201000009910 diseases by infectious agent Diseases 0.000 claims description 9
- 206010013023 Diphtheria Diseases 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
- 125000005493 quinolyl group Chemical group 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 244000005700 microbiome Species 0.000 claims description 7
- 206010024229 Leprosy Diseases 0.000 claims description 6
- 206010029444 Nocardiosis Diseases 0.000 claims description 6
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 229910052805 deuterium Inorganic materials 0.000 claims description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 5
- 229940113083 morpholine Drugs 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 5
- 239000003638 reducing agent Substances 0.000 claims description 5
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
- HONIICLYMWZJFZ-UHFFFAOYSA-N Azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 206010060945 Bacterial infection Diseases 0.000 claims description 3
- HXJUTPCZVOIRIF-UHFFFAOYSA-N Sulfolane Chemical group O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 3
- BRNULMACUQOKMR-UHFFFAOYSA-N Thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 239000000546 pharmaceutic aid Substances 0.000 claims description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 3
- 230000002685 pulmonary Effects 0.000 claims description 3
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
- 125000005418 aryl aryl group Chemical group 0.000 claims description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- BNMSJUIMZULLAS-UHFFFAOYSA-N 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine Chemical compound N1=CC(C(F)(F)F)=CC=C1N1CCNCC1 BNMSJUIMZULLAS-UHFFFAOYSA-N 0.000 claims 1
- 241001024304 Mino Species 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 177
- 239000000243 solution Substances 0.000 description 84
- 239000002585 base Substances 0.000 description 79
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 68
- 238000004949 mass spectrometry Methods 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
- 239000000047 product Substances 0.000 description 48
- 239000012074 organic phase Substances 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- 235000019253 formic acid Nutrition 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 38
- 235000019439 ethyl acetate Nutrition 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 31
- 238000003756 stirring Methods 0.000 description 31
- 239000002609 media Substances 0.000 description 27
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 239000000377 silicon dioxide Substances 0.000 description 24
- 238000004587 chromatography analysis Methods 0.000 description 23
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- 239000000543 intermediate Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- JQWHASGSAFIOCM-UHFFFAOYSA-M Sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- 239000008346 aqueous phase Substances 0.000 description 18
- 239000011780 sodium chloride Substances 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
- 239000012429 reaction media Substances 0.000 description 16
- 150000003839 salts Chemical class 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 239000002244 precipitate Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 235000015320 potassium carbonate Nutrition 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 11
- 125000004432 carbon atoms Chemical group C* 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000010828 elution Methods 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 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
- 125000006239 protecting group Chemical group 0.000 description 10
- 230000002829 reduced Effects 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- HCUYBXPSSCRKRF-UHFFFAOYSA-N Diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 9
- 238000000855 fermentation Methods 0.000 description 9
- 230000004151 fermentation Effects 0.000 description 9
- 150000002678 macrocyclic compounds Chemical class 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- 229960001456 Adenosine Triphosphate Drugs 0.000 description 6
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 6
- JQXXHWHPUNPDRT-ZNQWNCHJSA-N O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)Nc2c(O)c3c(O)c4C)C)OC)c4c1c3c(O)c2C=NN1CCN(C)CC1 Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)Nc2c(O)c3c(O)c4C)C)OC)c4c1c3c(O)c2C=NN1CCN(C)CC1 JQXXHWHPUNPDRT-ZNQWNCHJSA-N 0.000 description 6
- 229940081190 Rifampin Drugs 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
- 229960001225 rifampicin Drugs 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 230000003115 biocidal Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000001963 growth media Substances 0.000 description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 5
- 125000003367 polycyclic group Chemical group 0.000 description 5
- 239000001184 potassium carbonate Substances 0.000 description 5
- 230000001681 protective Effects 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 4
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 4
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 4
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N Benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 4
- 241000186359 Mycobacterium Species 0.000 description 4
- 229910020175 SiOH Inorganic materials 0.000 description 4
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 4
- 230000000798 anti-retroviral Effects 0.000 description 4
- 230000001580 bacterial Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- 229940079866 intestinal antibiotics Drugs 0.000 description 4
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 238000004450 types of analysis Methods 0.000 description 4
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 101710014631 CHURC1 Proteins 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N Carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 241000186216 Corynebacterium Species 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- QRXWMOHMRWLFEY-UHFFFAOYSA-N Isoniazid Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 3
- 206010062207 Mycobacterial infection Diseases 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial Effects 0.000 description 3
- 230000000845 anti-microbial Effects 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 230000003385 bacteriostatic Effects 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 229960003350 isoniazid Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004434 sulfur atoms Chemical group 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- 125000004326 2H-pyran-2-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])(*)O1 0.000 description 2
- 241001540743 Allokutzneria albata Species 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 102100004057 CYP3A4 Human genes 0.000 description 2
- 101710007540 CYP3A4 Proteins 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- AEUTYOVWOVBAKS-UWVGGRQHSA-N Ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 2
- 229960000285 Ethambutol Drugs 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 108060001084 Luciferase family Proteins 0.000 description 2
- 230000036740 Metabolism Effects 0.000 description 2
- OKDQKPLMQBXTNH-UHFFFAOYSA-N N,N-dimethyl-2H-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N Nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 208000008128 Pulmonary Tuberculosis Diseases 0.000 description 2
- IPEHBUMCGVEMRF-UHFFFAOYSA-N Pyrazinamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 2
- 229960005206 Pyrazinamide Drugs 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N Sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- 229940031000 Streptococcus pneumoniae Drugs 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N Tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- MWOOGOJBHIARFG-UHFFFAOYSA-N Vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000005842 heteroatoms Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 230000002503 metabolic Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000035786 metabolism Effects 0.000 description 2
- 230000002906 microbiologic Effects 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 125000004430 oxygen atoms Chemical group O* 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000000275 pharmacokinetic Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 230000000241 respiratory Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 201000006382 tuberculoid leprosy Diseases 0.000 description 2
- OKTJSMMVPCPJKN-IGMARMGPSA-N (12)6C Chemical compound [12C] OKTJSMMVPCPJKN-IGMARMGPSA-N 0.000 description 1
- UORYDCSVHJNLHE-LBPRGKRZSA-N (5R)-5-[[4-(aminooxymethyl)triazol-1-yl]methyl]-3-(3-fluorophenyl)-1,3-oxazolidin-2-one Chemical compound N1=NC(CON)=CN1C[C@@H]1OC(=O)N(C=2C=C(F)C=CC=2)C1 UORYDCSVHJNLHE-LBPRGKRZSA-N 0.000 description 1
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 description 1
- PKORYTIUMAOPED-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC=C2NCNCC2=C1 PKORYTIUMAOPED-UHFFFAOYSA-N 0.000 description 1
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- LPAGFVYQRIESJQ-UHFFFAOYSA-N 2,3-dihydro-1H-indole Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 description 1
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 1
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 1
- YRRZGBOZBIVMJT-UHFFFAOYSA-N 2-fluoroethanamine;hydron;chloride Chemical compound Cl.NCCF YRRZGBOZBIVMJT-UHFFFAOYSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- IDLHTECVNDEOIY-UHFFFAOYSA-N 2-pyridin-4-ylethanamine Chemical compound NCCC1=CC=NC=C1 IDLHTECVNDEOIY-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- SPQRFMQNZSLTCV-UHFFFAOYSA-N 3,6-diazabicyclo[3.1.0]hexane Chemical compound C1NCC2NC12 SPQRFMQNZSLTCV-UHFFFAOYSA-N 0.000 description 1
- XFDUHJPVQKIXHO-UHFFFAOYSA-N 3-Aminobenzoic acid Chemical compound NC1=CC=CC(C(O)=O)=C1 XFDUHJPVQKIXHO-UHFFFAOYSA-N 0.000 description 1
- CPBZARXQRZTYGI-UHFFFAOYSA-N 3-cyclopentylpropylcyclohexane Chemical compound C1CCCCC1CCCC1CCCC1 CPBZARXQRZTYGI-UHFFFAOYSA-N 0.000 description 1
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 1
- 210000004100 Adrenal Glands Anatomy 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N Azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 241000304886 Bacilli Species 0.000 description 1
- JYZIHLWOWKMNNX-UHFFFAOYSA-N Benzimidazole Chemical compound C1=C[CH]C2=NC=NC2=C1 JYZIHLWOWKMNNX-UHFFFAOYSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N Benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N Benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N Benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N Benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- 210000000988 Bone and Bones Anatomy 0.000 description 1
- 210000000621 Bronchi Anatomy 0.000 description 1
- NDVZWDMTLCTMCE-HHVUZZQSSA-N CC(CC(=O)OC1C(C(OCCC(CCCCCCC1)O[C@H]1C[C@H](N(C[C@@H](O1)C)C)C)=O)=O)C Chemical compound CC(CC(=O)OC1C(C(OCCC(CCCCCCC1)O[C@H]1C[C@H](N(C[C@@H](O1)C)C)C)=O)=O)C NDVZWDMTLCTMCE-HHVUZZQSSA-N 0.000 description 1
- YIYMCJDWGCWRDX-UHFFFAOYSA-N CC(CC(=O)OC1C(C(OCCCCCCCCCC1)=O)=O)C Chemical compound CC(CC(=O)OC1C(C(OCCCCCCCCCC1)=O)=O)C YIYMCJDWGCWRDX-UHFFFAOYSA-N 0.000 description 1
- ADCNUBTZQXXBGD-IURZNPLQSA-N CC(CC(=O)OC1C(COC(C(C(C(CC(CC(C(C1C)=O)C)C)C)O[C@H]1CC(N(C[C@@H](O1)C)C)C)C)=O)C)C Chemical compound CC(CC(=O)OC1C(COC(C(C(C(CC(CC(C(C1C)=O)C)C)C)O[C@H]1CC(N(C[C@@H](O1)C)C)C)C)=O)C)C ADCNUBTZQXXBGD-IURZNPLQSA-N 0.000 description 1
- FAFRXHZAHZLVDI-UHFFFAOYSA-N CC(CC(=O)OC1C(COC(C(CC(CC(CC(C(C1C)=O)C)C)C)C)=O)C)C Chemical compound CC(CC(=O)OC1C(COC(C(CC(CC(CC(C(C1C)=O)C)C)C)C)=O)C)C FAFRXHZAHZLVDI-UHFFFAOYSA-N 0.000 description 1
- 229940041514 Candida albicans extract Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- QYNCOIYMTGYJBF-UHFFFAOYSA-N Cl.Cl.CC(C)(N)CNS(=O)(=O)c1cn[nH]c1[N+]([O-])=O Chemical compound Cl.Cl.CC(C)(N)CNS(=O)(=O)c1cn[nH]c1[N+]([O-])=O QYNCOIYMTGYJBF-UHFFFAOYSA-N 0.000 description 1
- 101710041556 Ctsq Proteins 0.000 description 1
- 206010011684 Cutaneous tuberculosis Diseases 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 210000004907 Glands Anatomy 0.000 description 1
- 240000007842 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 240000008669 Hedera helix Species 0.000 description 1
- 206010021700 Indeterminate leprosy Diseases 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N Isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N Isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 210000000867 Larynx Anatomy 0.000 description 1
- 206010065048 Latent tuberculosis Diseases 0.000 description 1
- 206010024227 Lepromatous leprosy Diseases 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 241000989747 Maba Species 0.000 description 1
- 229940045184 Malt extract Drugs 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 241000539716 Mea Species 0.000 description 1
- 208000001223 Meningeal Tuberculosis Diseases 0.000 description 1
- 206010027259 Meningitis tuberculous Diseases 0.000 description 1
- 230000035633 Metabolized Effects 0.000 description 1
- UUIQMZJEGPQKFD-UHFFFAOYSA-N Methyl butyrate Chemical compound CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 1
- 241001467553 Mycobacterium africanum Species 0.000 description 1
- 241000186366 Mycobacterium bovis Species 0.000 description 1
- 241000186362 Mycobacterium leprae Species 0.000 description 1
- 241000187481 Mycobacterium phlei Species 0.000 description 1
- 241000187480 Mycobacterium smegmatis Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 229940010383 Mycobacterium tuberculosis Drugs 0.000 description 1
- UUUQVZOMXZERFR-UHFFFAOYSA-N N-(2-amino-2-methylpropyl)-2-nitrobenzenesulfonamide;hydrochloride Chemical compound Cl.CC(C)(N)CNS(=O)(=O)C1=CC=CC=C1[N+]([O-])=O UUUQVZOMXZERFR-UHFFFAOYSA-N 0.000 description 1
- YTPFQIONTWQEBX-UHFFFAOYSA-N N-(2-amino-2-methylpropyl)benzenesulfonamide;hydrochloride Chemical compound Cl.CC(C)(N)CNS(=O)(=O)C1=CC=CC=C1 YTPFQIONTWQEBX-UHFFFAOYSA-N 0.000 description 1
- 241000187654 Nocardia Species 0.000 description 1
- 241001503696 Nocardia brasiliensis Species 0.000 description 1
- 102100018344 PRPF3 Human genes 0.000 description 1
- 101700055558 PRPF3 Proteins 0.000 description 1
- 206010053583 Peritoneal tuberculosis Diseases 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N Phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N Pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N Quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N Quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 1
- 101710005260 RPL6A Proteins 0.000 description 1
- 101710005264 RPL6B Proteins 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 210000004304 Subcutaneous Tissue Anatomy 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N THP Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- UWYZHKAOTLEWKK-UHFFFAOYSA-N Tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N Tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 210000003437 Trachea Anatomy 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N Trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- XLRPYZSEQKXZAA-OCAPTIKFSA-N Tropane Chemical compound C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 description 1
- 208000008744 Tuberculous Peritonitis Diseases 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N VANCOMYCIN Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 Vancomycin Drugs 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920005549 butyl rubber Polymers 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- LMLOMPMKDILPOS-UHFFFAOYSA-N carbonochloridic acid;trichloromethyl carbonochloridate Chemical compound OC(Cl)=O.ClC(=O)OC(Cl)(Cl)Cl LMLOMPMKDILPOS-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005824 corn Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 201000003107 cutaneous diphtheria Diseases 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- QPMLSUSACCOBDK-UHFFFAOYSA-N diazepane Chemical compound C1CCNNCC1 QPMLSUSACCOBDK-UHFFFAOYSA-N 0.000 description 1
- YRTMEEURRDTMST-UHFFFAOYSA-N diazetidine Chemical compound C1CNN1 YRTMEEURRDTMST-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 201000006674 extrapulmonary tuberculosis Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003260 fluorescence intensity Methods 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WJDMEHCIRPKRRQ-UHFFFAOYSA-N furo[3,2-c]pyridine Chemical compound N1=CC=C2OC=CC2=C1 WJDMEHCIRPKRRQ-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000002440 hepatic Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 201000008267 intestinal tuberculosis Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N iodine atom Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 201000007227 lymph node tuberculosis Diseases 0.000 description 1
- 230000001926 lymphatic Effects 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 239000003607 modifier Chemical group 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- JYAQWANEOPJVEY-LYFYHCNISA-N mycarose Chemical compound C[C@H](O)[C@H](O)[C@](C)(O)CC=O JYAQWANEOPJVEY-LYFYHCNISA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940005931 ophthalmologic Fluoroquinolone antiinfectives Drugs 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001717 pathogenic Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 230000002285 radioactive Effects 0.000 description 1
- 239000002824 redox indicator Substances 0.000 description 1
- HSSLDCABUXLXKM-UHFFFAOYSA-N resorufin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3N=C21 HSSLDCABUXLXKM-UHFFFAOYSA-N 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000001954 sterilising Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229940041075 systemic Fluoroquinolone antibacterials Drugs 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N tetrahydro-2H-thiopyran Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 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
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000000725 trifluoropropyl group Chemical group [H]C([H])(*)C([H])([H])C(F)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229940117960 vanillin Drugs 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Abstract
The patent application relates to compounds of formula (I) below:
Description
Macrollde dérivatives, préparation thereof and therapeutic use thereof
The présent invention relates to macrolide dérivatives, and to the préparation and therapeutic use thereof. The compounds according to the présent invention hâve 5 substantial antimicrobial activity, mainly on gram-positive microorganisms, and also on mycobacteria, especially in the treatment of tuberculosis.
Due to the appearance of résistance, the development of novel antibacterial agents Is necessary to make it possible to kill or to prevent the growth of mycobacteria, 10 especially those which induce tuberculosis.
Tuberculosis Is a disease which, at the présent time, is still a worldwide health threat. Globally, a third of the human population is infected with Mycobacterium tuberculosis. Despite the fact that treatments exist and that the disease is curable, 15 tuberculosis killed approximately 1.82 million people In 2008, and its global incidence increases by 1% per year, with an estimation in 2008 of 9.4 million annual new cases of declared disease. Added to this are the difficulties of correct prescription and of adhérence to the treatment protocole, and also the emergence of multi-resistant strains of M. tuberculosis. Drug-drug Interactions also interfère with the optimum treatment of AIDS 20 and tuberculosis In the case of co-infected patients.
The common treatment protocols for combating sensitive strains of M. tuberculosis are mainly based on a combination of three or, more frequently, of four molécules: isoniazide (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB). These drugs constitute the first-line treatment.
In recent décades, tuberculosis has become résistant to each of these molécules.
Strains that are résistant at least to isoniazide and to rifampicin are referred to as multiresistant (MDR-TB). Recently, novel strains hâve appeared which are résistant to a larger number of molécules: those that are résistant to isoniazide, to rifampicin, to fluoroquinolones and to at least one injectable second-line drug are defined as being 30 ultra-résistant (XDR-TB).
According to an estimation made by the WHO in 2009, there were 0.5 million cases of MDR-TB In 2007. Other évaluations report a relative incidence of about 11% of multi-resistant strains among ail new cases of tuberculosis.
Another therapeutic drawback in the treatment of tuberculosis is the interaction of 35 rifampicin with treatments for combating HIV (human immunodeficiency virus), which represents an obstacle In the treatment of patients co-infected with tuberculosis and HIV. The current anti-HIV therapeutic recommendations favour, as a first-line treatment, an anti-retroviral triple therapy combining a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRT1) with two nucleoside reverse transcriptase inhibitors (NRTI). PI and NNRTI are metabolized by CYP3A4. Metabolic interactions between anti-retrovirals (ATRV) and certain combined drugs hâve been demonstrated. Thus, rifampicin, which is a powerful inducer of intestinal and hepatic CYP3A4, reduces the concentrations of ATRV.
There is an urgent need to develop improved thérapies for combating tuberculosis. These novel anti-tuberculosis treatments should be capable of satisfying one or more of the following criteria:
• shorten the treatment time to improve the adhérence to the treatment pratocols and reduce the appearance of résistant bacteria, • be well tolerated, acting via novel mechanisms of action and thus effective against multl-resistant and/or ultra-résistant strains, • be active against tuberculosis, • hâve a shortened latent tuberculosis (asymptomatic first infection) treatment time, so as to address the problem of the biological réservoir of M. tuberculosis.
FR 2 126 108 and Amoux et al. (Journal of the American Chemical Society 102(10), 1980, 3605) describe sequanamycin (A), having the following formula:
(3S,4S,5R,7S,9S,10S,11R,12S,13R)-12-[(4,5-dihydroxy-4,6-dimethyltetrahydro2H-pyran-2-yl)oxy]-7-hydroxy-2-{1-I(5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2Hpyran-2-yl)oxy]propan-2-yl}-10-[(3-hydroxy-6-methyl-4-oxotetrahydro-2H-pyran-2-yl)oxyJ-
3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl) 3-methylbutanoate.
This compound is described therein as an antimicrobial agent and especially enables the treatment of tuberculosis. However, this compound may show instabiiity, in particular in acldic or basic aqueous medium, and/or may also show metabolic instabiiity, which makes it difftcult to use as a drug.
‘i
It is therefore necessary to develop compounds with improved and/or more active pharmacokinetic properties, so as to enable their use as médicaments.
A subject of the présent invention is in particular macrolide dérivatives, which hâve bacteriostatic and/or bactericidal action, mainly on gram-positive microorganisms, and also on mycobacteria, especially against strains of sensitive Mycobacterium or Corynebacterium that are résistant to the first-line antibiotics, and the préparation and therapeutic uses thereof.
[COMPOUNDS]
The présent invention relates to compounds corresponding to formula (I):
in which:
- Y represents a hydrogen atom, a group -(C=O)-NR2R3 or a group -(C=O)-O-Ris;
- Z represents:
• a hydrogen atom, • a group -Ci^-alkyl, which is unsubstituted or substituted with one or more groups R«, • a group -C3.7-cycloalkyl, which is unsubstituted or substituted with a group -NH(C-O)-Rw or with a group -NH-SO2-R20, • a group -Cs^-heterocycloalkyl, • a group -NH-(C=O)-R5;
• I *ύ
Ri represents a hydrogen atom, a group -C2-e-alkeny1, a group -C2-e-alkynyl or a group -Ci-e-alkyl which is unsubstituted or substituted with a group -Cmfluoroalkyl or with a heteroaryl group which is unsubstituted or substituted with a group 3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-ylmethyl;
R2 represents a hydrogen atom or a group -Ci-e-alkyl;
R3 represents:
• a group -C3-7-cycloalkyl, which is unsubstituted or substituted with a group -C 1-3-alkyl substituted with a group -NH-SO2-R21, • a heteroaryl group, • a linear or branched group -Ci-e-alkyl, which is unsubstituted or substituted with a group chosen from:
• a group -NH-Re, • a group -NH-SO2-R7, • a group -NH-(C=O)-R8, • a group -C3-7-cycloalkyl, which is unsubstituted or substituted with a group -C3-6-heterocycloalkyl, • a group -C3-6-heterocycloalkyl, • an aryl group, which is unsubstituted or substituted with one or more groups chosen independently from a halogen atom and a group -C1-4fluoroalkyl, • a heteroaryl group, which is unsubstituted or substituted with a group -Ci-3-alkyl, a group -Ci-4-alkoxy, a group -C 1-4-fluoroalkyl or a group -C3-e-heterocycloalky1, • or altematively with one or more groups -Ci-4-alkoxy;
or altematively R2 and R3, together with the nitrogen atom to which they are attached, constitute a group -C3-e-heterocycloalky1 chosen from: aziridine, azetidine, pyrrolidine, pi pend in e, morpholine, thiomorpholine or piperazine; the said heterocycloalkyl group being unsubstituted or substituted with a heteroaryl group, the said heteroaryl group being unsubstituted or substituted with a group -Ci-4-fluoroalkyl;
R4 independently represents a group chosen from:
• a hydroxyl group, • a deuterium, • a halogen atom, • a group -Cs-7-cycloalkyl, • an aryl group, which is unsubstituted or substituted with one or more groups -Rs, • a heteroaryl group, • a group -C3-6-heterocycloalkyl, • a group -Ci-4-alkoxy, • a group -(C=O)-NH-Rw, • a group-NH-Rn, • a group -NH-(C=O)-Ri2, • or a group -NH(SO2)-R13;
Rs represents a heteroaryl group;
Re represents a heteroaryl group, which is unsubstituted or substituted with one or more halogen atoms;
R7 represents a group -Ci-4-fluoroalkyl, an aryl group or a heteroaryl group, the said aryl and heteroaryl groups being unsubstituted or substituted with one or more groups Rr;
Re represents a heteroaryl group, which is unsubstituted or substituted with one or more groups Rz;
Rg represents a halogen atom, a group -Ci-4-alkoxy, a formyl group (CHO) or a group -Ci-4-alkyl, which is unsubstituted or substituted with a hydroxyl group;
Rio represents a heteroaryl group, which is unsubstituted or substituted with a group -Ci-3-alkyl;
R11 represents:
• a group -CsdO-heterocycloalkyl, which is unsubstituted or substituted with one or more oxide groups, ,ί ·♦ * » • a heteroaryi group or an aryl-Ci-4-alkyl group, the said heteroaryi or aryl groups being unsubstituted or substituted with one or more groups independently chosen from a halogen atom, a hydroxyl group, a nitro group and a group -Ci-3-alkyl;
- R12 represents:
• a group -Ci-4-alkoxy, • a group -Ci-4-atkyl, which is unsubstituted or substituted with a group -NR14R15 or with a heteroaryi group, the said heteroaryi group being unsubstituted or substituted with a group -Ci-3-alkyl, • a heteroaryi group, which is unsubstituted or substituted with one or more groups chosen from a hydroxyl group and a group -Ci-3-alkyl;
- R13 represents:
• a group -Ci-4-alkyl, • a group -Ci-4-fluoroalkyl, • an aryl group, which is unsubstituted or substituted with a nitro group, • or a heteroaryi group, which Is unsubstituted or substituted with a group -NR16R17;
- Rt4, R15, R16 and R17 each independently represent:
• a hydrogen atom, • or a group -Ci-4-alkyl;
- Rie represents a group -Ci-4-alkyl or a benzyl group;
- R19 represents an aryl group or a heteroaryi group;
- R20 represents a group -Ci-4-alkyl or an aryl group;
- R21 represents an aryl group;
- Rr represents:
• a halogen atom, • a group -Ci-4-alkoxy, • a group -Ci-4-fluoroalkyl, • a group -OCF3, • a nitro group, • a group -NH2, • a group-NHCH3;
- R2‘ represents:
• a hydroxyl group, • a group -Ci-e-alkyl.
The compounds of general formula (I) may comprise one or more asymmetric carbons. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and also mixtures thereof, induding racemic mixtures, form part of the invention.
The compounds of formula (I) may exist in the form of bases or acid-addition salts. Such addition salts form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids, but salts of other acids, for example for purifying or isolating the compounds of general formula (I). also form part of the invention.
The compounds of formula (I) according to the présent invention also comprise those in which one or more hydrogen, carbon or halogen atoms, especially chlorine or fluorine atoms, hâve been replaced with their radioactive isotopes, for example deuterium or tritium to replace hydrogen or carbon-14 to replace carbon-12. Such labelled compounds are useful in research, metabolism or pharmacokinetic studies, and also in biological and pharmacological tests as tools.
In the context of the présent invention:
• alkyl represents a saturated, linear or branched aliphatic group; for example, a group Ci-3-alkyl represents a linear or branched carbon-based chain of 1 to 3 carbon atoms, especially a methyl, ethyl, propyl or isopropyl. Similarly, a group Ci-4-alkyl represents a linear or branched carbon-based chain of 1 to 4 carbon atoms, especially a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, seobutyl or tert-butyl. Similarly, a group Ci-ealkyl represents a linear or branched carbon-based chain of 1 to 6 carbon atoms, especially a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, seobutyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl or isohexyl.
.1 > *1 • alkenyl represents a linear or branched hydrocarbon-based aliphatic group comprising at least one unsaturation in the form of a double bond, and comprising from 2 to 6 carbon atoms. Examples that may be mentioned include the vinyl and allyl groups.
• alkynyl represents a linear or branched hydrocarbon-based aliphatic group comprising at least one unsaturation in the form of a triple bond, and comprising from 2 to 6 carbon atoms. Examples that may be mentioned Include the ethynyl and 2-propynyl groups.
• cycloalkyl represents a saturated cyclic aliphatic group comprising from 3 to 7 carbon atoms. Examples that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
• halogen represents a fluorine, chlorine, bromine or iodine atom.
• fluoroalkyl represents an alkyl group comprising from 1 to 4 carbon atoms, in which one or more hydrogen atoms are replaced with' a fluorine atom. Examples of fluoroalkyl groups that may be mentioned include trifluoromethyl, difluoromethyl, 3,3,315 trifluoropropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2,3,3-tetrafluoropropyl, 1,1difluoroethyl and 3,3,3-trifluoro-2-(trifluoromethyl)propyl.
• heterocycloalkyl represents a saturated or partially saturated, monocyclic or polycyclic, optionally substituted 3- to 9-membered ring including one or more heteroatoms such as nitrogen, oxygen or sulfur atoms. The sulfur atoms may be in the form of sulfoxide or sulfone. By way of example, a heterocycloalkyl may be a pyrrolidine, a morpholine, a piperazine, a diazetidine, a dihydropyrrolidine, a piperidine, an azepane, an imidazolidine, a thiomorpholine, a tetrahydropyran, a tetrahydrothiophene, a tetrahydrothiopyran, a diazepane or an azabicyclooctane, a tropane, a 3,6diazabicyclo[3.1.0]hexane, a tetrahydrofuran, a 3,7-diazabicycloi3.3.1]nonane or a 25 tetrahydrothiophene 1,1-dioxide.
• aryl represents a monocyclic or polycyclic, optionally substituted aromatic system comprising from 6 to 14 carbon atoms. According to one embodiment of the invention, the aryl group comprises 6 to 10 carbon atoms. When the system is polycyclic, at least one of the rings is aromatic. Examples of aryl groups that may be mentioned include phenyl, naphthyl, indanyl, tetrahydronaphthyl, anthracenyl and azulenyl.
• heteroaryl represents a monocyclic or polycyclic, optionally substituted 5- to 14membered aromatic system. According to one embodiment of the invention, the heteroaryl Is 5- to 10-membered and comprises one or more heteroatoms such as nitrogen, oxygen or sulfur atoms. When the system is polycyclic, at least one of the rings is aromatic. Examples of monocyclic heteroaryls that may be mentioned include thiazole, thiadiazole, thiophene, imidazole, triazole, tetrazole, pyridine, furan, oxazole, isoxazole, oxadiazole, pyrrole, pyrazole, pyrimidine, pyridazine and pyrazine. Examples of polycyclic heteroaryls that may be mentioned include indole, benzofuran, benzimidazole, benzothiophene, benzotriazole, benzothiazole, benzoxazole, quinoline, isoquinoline, indazole, quinazoline, phthalazine, quinoxaline, naphthyridine,
2,3-dihydro-1H-indole, 2,3-dihydrobenzofuran, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydroisoquinazoline, furo[3,2-c]pyridine, 1/-/-pyrrolo[2,3bjpyridine or tetrahydroquinazoline.
• alkoxy represents a group O-alkyl containing a saturated, linear or branched aliphatic chain comprising 1 to 4 carbon atoms. Examples of alkoxy groups that may be mentioned include methoxy and ethoxy.
According to the présent invention, distinguished compounds are those of formula (I) in which Y represents a group -(C=O)-NR2R3, of formula:
in which Ri, R2, R3 and Z are as defined for the compounds of formula (I);
in the form of bases or of acid-addition salts.
According to the présent invention, distinguished compounds are also those of formula (I) in which Y represents a hydrogen atom, of formula:
ίο
(IB)
In which Ri and Z are as defined for a compound of formula (I); in the form of bases or of acid-addition salts.
According to a first variant of formula (IA), R2 represents a hydrogen atom and R3 represents a linear Ct-e-alkyl (Alk), which is unsubstituted or substituted with a group as defined for the compounds of formula (I), the compounds then having the formula (IC) below:
in which Ri and Z are as defined for the compounds of formula (I);
in the form of bases or of acid-addition salts.
π
Within the compounds of formula (IC), distinguished compounds are those of formula (ID) below in which Alk represents a methyl substituted with a phenyl group:
and Ri and Z are as defined for a compound of formula (I);
in the form of bases or of acid-addition salts.
According to a second variant of formula (IA), distinguished compounds are those of formula (IE) in which R2 represents a hydrogen atom and R3 represents a branched C-i-e-alkyl (-C(CH3)2-Alk’), which is unsubstituted or substituted with a group as defined for 10 the compounds of formula (I):
and Ri and Z are as defined for the compounds of formula (I);
in the form of bases or of acid-addition salts.
I2
Within the compounds of formula (IE), distinguished compounds are those of formula (IG) below in which Alk* represents a [(phenylsulfonyl)aminojmethyl group:
o
and Ri and Z are as defined for the compounds of formula (I); in the form of bases or of acid-addition salts.
According to a third variant of formula (IA), R2 and R3 represent an unsubstituted group -Ci-e-alkyl (Alk), the compounds then having the formula (IF) below:
in which Ri and Z are as defined for a compound of formula (I);
in the form of bases or of acid-addition salts.
According to a fourth variant of formula (IA), R2 represents a hydrogen atom and
R3 represents an unsubstituted group -C3-7-cycloalkyl (cycloAlk), the compounds then having the formula (IH) below:
in which Ri and Z are as defined for a compound of formula (I); in the form of bases or of acid-addition salts.
According to the présent invention, distinguished compounds are also those of formula (I) in which Y represents a group -(C=O)-ORi8, of formula:
In which Ri, Rie and Z are as defined for a compound of formula (I);
In the form of bases or of acid-addition salts.
.» ·*
According to the présent invention, distinguished compounds are those of formula (I) in which:
- Y represents a hydrogen atom, a group -(C=O)-NR2R3 or a group -(C=O)-OMe;
- Z represents:
• a hydrogen atom, • a group -Ci-e-alkyl, which is unsubstituted or substituted with one or more groups R4, • a cyclopropyl group, a cydobutyl group, a 3-(benzoylamino)cyclobutyl group, a
3-[(pyrazin-2-ylcarbonyl)amino]cyclobutyl group, a 3-[(methylsulfonyl)amino] cydobutyl group, a 3-[(phenylsulfonyl)amino]cyclobutyl group, a cyclopentyl group, a cyclohexyl group, • a tetrahydro-2H-pyranyl group, • a group -NH-(C=O)-R5;
- Ri represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethyl group or a methyl group, which is unsubstituted or substituted with a 1,2,3-triazole group substituted with a 3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-ylmethyl group;
- R2 represents a hydrogen atom or a methyl group;
- R3 represents:
• a cyclohexyl group, a 1-{[(phenylsulfonyl)amino]methyl}cyclohexyl group or a
1-{[(phenylsulfonyl)amino]methyl}cyclopentyl group, • a 5,6,7,8-tetrahydroquinolin-5-yl group, • or a linear or branched group Ci-4-alkyl, which Is unsubstituted or substituted with a group chosen from:
• -NH-Re, • -NH-SO2-R7, • -NH-(C=O)-R8, • a 1-morpholin-4-ylcyclopentyl group, • a tetrahydro-2H-pyranyl group, a tetrahydrofuranyl group or a morpholin-4-yl group, • a phenyl group, which is unsubstituted or substituted with one or more groups chosen independently from a chlorine atom and a group -CF3, .* ·* • a 1H-pyrrolo[2,3-b]pyridinyl group, a 4-methyl-5,6,7,8tetrahydroquinazolin-2-yl group, a 6-methoxy-1H-benzimidazol-2-yl group, a pyridinyl group, which is unsubstituted or substituted with a group -CF3 or with a morpholin-4-yl group, • or altematively with one or more methoxy groups;
- or altematively R2 and R3, together with the nitrogen atom to which they are attached, constitute a -C^-e-heterocycloalkyl group chosen from: azetidine, morpholine, 4-[5-(trifluoromethy1)pyridin-2-ylÎpiperazine;
- R4 independently represents a group chosen from:
• a hydroxyl group, • a deuterium, • a fluorine atom, • a cyclopropyl group, • a phenyl group, which is unsubstituted or substituted with one or more groups chosen independently from a fluorine atom, a methoxy group, a -CH2OH group and a -CHO group, • a pyridyl group, • a morpholinyl group, a tetrahydro-2H-pyranyl group, • a methoxy group, • a group -(C=0)-NH-Rio, • a group-NH-R11, • a group -NH-(C=O)-Ri2, • or a group -NH(SO2)-Ri 3;
- Rs represents a pyridyl group;
- Rs represents a quinolyl group, the said quinolyl group being unsubstituted or substituted with a chlorine atom;
- R7 represents a -CF3 group, a phenyl, pyridyl, pyrazolyl, 1H-pyrrolo[2,3-b]pyridyl or indolyl group, the said phenyl, pyridyl, pyrazolyl, 1H-pyrrolo[2,3-b]pyridyl or indolyl groups being unsubstituted or substituted with one or more groups Rr;
- Re represents a pyrazinyl group, the said pyrazinyl group being unsubstituted or substituted with one or more groups Rz;
.*
- Rio represents a 1,8-naphthyridinyl group substituted with a methyl group;
- R11 represents a tetrahydrothiophene-1,1-dioxide, quinolyl, pyridyl or benzyl group, the said quinolyl, pyridyl or benzyl groups being unsubstituted or substituted with a chlorine atom, a hydroxyl group, a nitro group or a methyl group;
- R12 represents:
• a tert-butoxy group, • a group -Cm-alkyl, which is unsubstituted or substituted with a group chosen from a group -NR14R15, pyridyl or pyrazolyl, the said pyridyl or pyrazolyl groups being unsubstituted or substituted with a methyl group, • a pyrazinyl or pyridyl, which is unsubstituted or substituted with one or more groups chosen from a hydroxy! group and a methyl group;
- Ri3 represents:
• a group -CF3, • a phenyl group, which is unsubstituted or substituted with a nitro group, • or a pyridyl group, which is unsubstituted or substituted with a group -NR16R17;
- Ri4, Ri 5, Rte and R17 each independentiy represent:
• a hydrogen atom, • a methyl group or an isopropy! group;
- Rr represents:
• a fluorine atom, a chlorine atom, • a methoxy group, • a group -CF3, • a group -OCF3, • a nitro group, • a group -NH2, • a group -NHCH3;
- R? represents:
• a hydroxyl group, • a methyl group;
in the form of bases or of acid-addition salts.
•i
According to the présent invention, distinguished compounds are those of formula (I) in which:
- Y represents a hydrogen atom or a group -(C=O)-NR2R3i
- Z represents:
• a hydrogen atom, • a methyl group, an Isopropyl group, a 2,2-dimethylpropyl group, • a group CD3, • a 2-fluoroethyl group, • a cyclopropylmethyl group, • a 2-phenylethyl group, • a [(7-methyl-1,8-naphthyridin-2-yl)amino]-4-oxobutyl group, • a 2-{[(2-nitrophenyl)sulfonyl]amino}ethyl group, • a cyclopropyl group, • a tetrahydro-2H-pyranyl group;
- Ri represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethyl group or a methyl group;
- R2 represents a hydrogen atom or a methyl group;
- R3 represents:
• a methyl group, • a 2-{[(2,6-difluorophenyl)sulfonyl]amino}-1,1-dimethylethyl group, • a 1,1-dimethyl-2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl group, • a 2-{[(2-fluorophenyl)sulfonyl]amino}-1,1-dimethylethyl group, • a 1,1-dimethyl-2-({[2-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl group, • a 1,1-dimethyl-2-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl group, • a 2-methyl-1-[(phenylsulfonyl)amino]propan-2-yl group, • a 2-methyl-1-{[(5-nitro-1H-pyrazol-4-yl)sulfonyl]amino}propan-2-yl group, • a 2-methyl-1-{{(trifluoromethyl)sulfonyl]amino}propan-2-yl group, • a 2-methyl-1-{[(2-nitrophenyl)sulfonyl]amino}propan-2-yl group, • a 1-{[(5-hydroxypyrazin-2-yl)carbonyl]amino}-2-methylpropan-2-yl group, • a 1,1 -dimethyl-2-morpholin-4-ylethyl group, • a benzyl group, • a 2-(4-pyridyl)ethyl group;
in the form of bases or of acid-addition salts.
.* ·»
Among the compounds according to the invention, mention may be made especially of the compounds below:
• (2R,3S,4R.5R,7S.9S.10S,11R.12S,13R)-7-[(benzylcarbamoyl)oxy]-2-(1{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-yl)-10-fl(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,5S,7R)-2,4,5trimethyl-1,4-oxazepan-7-yl]oxy)oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-2(1{[(2R,3R,4R,5R16R)-5-hydroxy-314-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-yl)-10-fl(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro2H-pyran-2-yl]oxy}-3l5,7,9,11,13-hexamethyl-6,14-dioxo-124((28^^)-2,4,5- tri methyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-{[(2S,7R)-4-cyclopropyl-2l5-dimethyl-1,4oxazepan-7-yl]oxy}-2-(1-{[(2R,3Rl4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7-{[(1-{[(5-hydroxypyrazin-2yl)carbonyl]amino}-2-methylpropan-2-yl)carbamoyl]oxy}-3,5,7l9I11,13-hexamethyl6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S, 10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,5R,7R)2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3I4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-2-(1-{[(2R13R,4R,5R,6R)-5-hydroxy-3,4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13hexamethyl-6,14-dioxo-7-({[2-(pyridin-4-yl)ethyl]carbamoyl}oxy)-12-{[(2Sl5S,7R)-2l4,5trimethyl-1,4-oxazepan-7-yl]oxy)oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S, 10S, 11 R, 12S, 13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2St7R)-4cyclopropyl-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3Rl4R,5R,6R)-5-hydroxy-
3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy)propan-2-yl)-10-{[(2S,3R,6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7)9,11,13hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9SI1 OS, 11 R,12S.13R)-7-[(benzylcarbamoyl)oxy]-12-i[(2S,7R)-2,5dimethyl-4-(2H3)methyl-1,4-oxazepan-7-yl]oxy}-2-(1-{I(2Rl3R,4Rl5Rl6R)-5-hydroxy-
3.4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3hydroxy'4-(methoxytmino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7l9111,13- hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4Rl5R,7S,9SI10S,11Rl12SI13R)-7-[(dimethylcarbamoyl)oxy]-2-(1{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-yl)-10-{[(2Sl3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro2H-pyran-2-yl]oxy}-3,5,7l9l11l13-hexamethyl-6,14-dioxo-12-{[(2Sl5R,7R)-2,4,5- trimethyl-1,4-oxazepan-7-ylJoxy)oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5Rl7S,9S,10S,11Rl12Sll3R)-7-[(benzylcarbamoyl)oxyJ-12-{[(2Sl7R)-2,5dimethyl-4-(2-[[(2-nitrophenyl)sulfonyl]amino}ethyl)-1(4-oxazepan-7-yl]oxy}-2-(1{[(2R,3R,4R15R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2ylJoxy}propan-2-yl)-10-{[(2S,3Rl6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-
2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3methylbutanoate;
• (2Rl3Sl4R,5R,7S,9Sl10S,11Rl12Sl13R)-7-[(benzylcarbamoyl)oxyJ-12-{[(2Sl7R)-4-(2fluoroethyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2Rl3R,4Rl5Rl6R)-5-hydroxy-
3.4- dimethoxy-6-methyltetrahydro-2H-pyran-2-ylJoxy}propan-2-yl)-10-{[(2Sl3Rl6R)-3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy)-3l5,7,9,11,13hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R15R,7S,9S,10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-Î[(2S,7R)-2,5dimethyl-4-(4-[(7-methyl-1,8-naphthyridin-2-yl)aminoJ-4-oxobutyl}-1,4-oxazepan-7yl]oxy}-2-(1-{[(2Rl3R(4R,5R,6R)-5-hydroxy-3l4-dimethoxy-6-methyltetrahydro-2H- pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3Rl6R)-3-hydroxy-4-(methoxyimino)-6methyltetrahydro-2H-pyran-2-ylJoxy}-3,5,7,9,11,13-hexamethyl-6,14dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,1 OS, 11 R,12S,13R)-7-[(benzylcart>amoyl)oxy]-12-{[(2S,7R)-4(2,2-dimethylpropyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3Rl4Rl5R,6R)-5- hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-
3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7SI9S,1 OS, 11 R,12S,13R)-12-{[(2S,7R)-2,5-dimethyl-4-(2-phenylethyl)-
1.4- oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3l4-dimethoxy-6.* ·* methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[{2S,3R,6R)-3-hydroxy-4(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7-([(1-([(5-hydroxypyrazin-2yl)carbonyl]amino}-2-methylpropan-2-yl)carbamoy!]oxy}-3,5,7,9,11,13-hexamethyl6,14-dioxooxacyctotetradecan-4-yt 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S, 10S, 11 R,12S,13R)-2-{1 -{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13hexamethyl-7-([(2-methyl-1-{I(5-nîtro-1H-pyrazol-4-yl)sulfonyl]amino}propan-2yl)carbamoyl]oxy}-6,14-dioxo-12-([(2S,7R)-2,4,5-trimethyt-1,4-oxazepan-7yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R, SS^R.SRJS.OS, 10S, 11 R, 12S.13R)-7-hydroxy-2-(1-{[(2R,3R,4R(5R,6R)-5hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-
3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-([(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7yl]oxy}oxacyclotetradecan-4-yl 3-methytbutanoate;
• (2R,3S,4R,5R,7S,9S,1 OS, 11 R,12S, 13R)-2-( 1 -{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3hydroxy-4-(methoxylmino)-6-methyttetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13hexamethyl-7-([(2-methyl-1-([(trifluoromethyl)sulfonyl]amîno}propan-2yl)carbamoyl]oxy}-6,14-dioxo-12-(I(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-([(2S,7R)-2,5-dimethyl-4-(2-phenylethyl)-
1,4-oxazepan-7-yl]oxy}-7-hydroxy-2-(1-([(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy6-methyltetrahydro-2H-pyran-2-yt]oxy}propan-2-yt)-10-{[(2S,3R,6R)-3-hydroxy-4(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yt]oxy}-3,5,7,9,11,13-hexamethyl-6,14dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11 R,12S, 13R)-2-(1 -{[(2R,3R,4R,5R,6R)-5-hydΓoxy-3,4dimethoxy-6-methyltetrahydro-2H-pyΓan-2-yl]oxy}propan-2-yl)-10-{I(2S,3R,6R)-3hydroxy-4-(methoxyimlno)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13hexamethyl-7-(I(2-methyt-1-{[(2-nitrophenyl)sutfonyt]amino}propan-2yOcarbamoylloxyJ-e.^-dioxo-^-flPS.SR.TR^AS-trimethyl-M-oxazepan-?yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S, 10S, 11 R,12S, 13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy)propan-2-yl)-10-{I(2S,3R,6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-315,7,9,11,13.» ·· hexamethyl-7-{[(2-methyl-1-{[(2-nitrophenyl)sulfonyl]amino}propan-2yl)carbamoyl]oxy}-6,14-dioxo-12-{[(2S,5Sl7R)-2,4l5-trimethyl-1l4-oxazepan-7yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4Rl5R,7S,9S,10S,11R,12S,13R)-2-(1-{((2Rl3R,4Rl5R16R)-5-hydroxy-3l4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy)propan-2-yl)-10-{[(2S,3R,6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13hexamethyl-7-[({2-methyl-1-[(phenylsulfonyl)amino]propan-2-yl}carbamoyl)oxy]-6,14dioxo-12-{[(2S,5S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl
3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,l0S,11R,12S,13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-104((2S,3R,6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5.7,9.11,13hexamethyl-7-[({2-methyl-1-[(pheny!sulfonyl)amino]propan-2-yl}carbamoyl)oxy]-6,14dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl
3-methylbutanoate;
• (2R,3S,4R.5Rl7Sl9S.10S,11R.12S.13R)-7-I({1,1-dimethyl-2[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{I(2S,3R,6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-12-{[(2S,7RHisopropy!-2,5-dimethyl-1 ,4-oxazepan-7-yl]oxy}-3,5,7,9, 11,13-hexamethyl-6,14dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S.11 R,12S. 13R)-12-{[(2S,5R,7R)-4-(cyclopropylmethyl)-2,5dîmethyl-1,4-oxazepan-7-yl]oxy}-7-[({1,1-dimethyl-2[(phenylsulfonyl)amino]ethyl)carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-lO-{[(2S,3Rt6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R, 3S,4R,5R,7S,9S. 10S, 11 R. 12S. 13R)-12-{[(2S,7R)-4-(cyclopropylmethyl)-2,5dimethyl-1,4-oxazepan-7-yl]oxy}-7-[({1,1 -dimethyl-2-[(phenylsulfonyl)amino]ethyl} carbamoyl)oxy]-2-(2-I[(2R.3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6- methy Itetra hydro-2 H-pyran-2-yl]oxy}-1 -m ethylethyl)-10-{[ (2S, 3R ,6 R)-3-hyd roxy-4(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[({1,1 -dimethyl-2-[(phenylsulfonyl)amino] ethyl)carbamoyl)oxy]-12-{[(2S,7R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,4 .· ·» oxazepan-7-yl]oxy}-2-(2-{[(2R,3R,4R15R,6R)-5-hydroxy-3,4-dimethoxy-6methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4(methoxyiminoJ-e-methyltetrahydro^H-pyran^-ylloxyJ-S.SJ.O.n.IS-hexamethyl-e,^ dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-([(2S,5S,7RH-(cyclopropylmethyl)-2(5dimethyl-1,4-oxazepan-7-yl]oxy}-7-[({1,1-dimethyl-2-[(phenylsulfonyl)amino]ethyl} carbamoyl)oxy]-2-(2-[[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro -2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R13S,4R,5R,7S19S, 10S, 11 R, 12S, 13 R)-7-(({1,1 -dimethyl-2[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-([(2S,5R,7R)-4-(2l2-dimethylpropyl)-
2,5-dÎmethyl-1,4-oxazepan-7-yl]oxy}-2-(2-([(2R,3R,4R,5Rl6R)-5-hydroxy-3,4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2Sl3R,6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R15R,7S,9S,10S,11R,12S,13R)-7-I({1,1-dimethyl-2[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-{[(2S17R)-4-(2l2-dimethylpropyl)-2,5dimethyl-1,4-oxazepan-7-yl]oxy}-2-(2-{[(2 R ,3R,4R ,5 R,6R)-5-hydroxy-3,4-dimethoxy-6methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4(methoxyimÎno)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7l9,11,13-hexamethyl-6,14dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S, 10S, 11 R, 12S, 13R)-7-[[( 1,1-dimethyl-2-morpholin-4ylethyl)carbamoyl]oxy}-2-(2-{[(2R,3R,4R,5R16R)-5-hydroxy-3,4-dimethoxy-6methyltetrahydro-2H-pyran-2-yl]oxy}-1-methytethyl)-10-{[(2S,3R,6R)-3-hydroxy-4(methoxyiminol-e-methyltetrahydro^H-pyran^-ylloxyl-S.SJ.gjl.lS-hexamethyl-O.Udioxo-12-{[(2S17R)-2,4,5-trimethyl-1l4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5Rl7S,9S,10S,1lR,12S,13R)-7-{[(2-{[(216-difluorophenyl)sulfonyl]amino}1,1-dimethylethyl)carbamoyl]oxy}-2-(2-[[(2Rl3Rl4R,5R16R)-5-hydroxy-3,4-dimethoxy6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3Rl6R)-3-hydroxy-4(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3l5,7,9,11,13-hexamethyl-6,14dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
.· ·· • (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-({[1 ,1-dimethyl-2-({[4-(trifluoromethyl) phenyl]sulfonyl}amino)ethyl]carbamoyl}oxy)-2-(2-{[(2R,3R,4R15R,6R)-5-hydroxy-314dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydrO'2H-pyran-2-yl]oxy}-3,5,7,9,11,13hexamethyl-6,14-dioxo-12-[[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy} oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5Rl7S,9S,10Sl11R,12S,13R)-7-{[(2-{[(2-fluorophenyl)sulfonyl]aminoH.1dimethylethyl)carbamoyl]oxy}-2-(2-{[(2R,3R,4Rl5R,6R)-5-hydroxy-314-dimethoxy-6methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14dioxo-12-([(2S,7R)-2,4l5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S,9S,1 OS, 11 R,12S,13R>-7-(« 1,1 -di methy l-2-({[2(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl]carbamoyl}oxy)-2-(2{[(2R13R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-
1-methylethyl)-10-([(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2Hpyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,1 OS, 11 R,12S.13R)-7-({[1,1-dimethyl-2-({[4(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl]carbamoyl}oxy)-2-(2{|(2R,3Rl4R,5Rl6R)-5-hydroxy-314-dîmethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-
1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2Hpyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2Rl3Sl4R,5R,7S,9S,10S,11R,12S,13R)-7-[({1,1-dimethyl-2[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-[[(2R,3R,4R,5R,6R)-5-hydroxy-3,4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-({(2S,3R,6R)-3hydroxy-6-methyl-4-[(2,2,2-trifluoroethoxy)iminoltetrahydro-2H-pyran-2-yl}oxy)-
3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[({1,1-dimethyl-2-[(phenylsulfonyl)amino] ethyl}carbamoyl)oxy]-10-{[(2S,3R,6R)-4-(ethoxyimino)-3-hydroxy-6-methyltetrahydro2H-pyran-2-yl]oxy}-2-(2-{[(2R,3R,4R15R,6R)-5-hydroxy-314-dimethoxy-6methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-3,5l7,9l11,13-hexamethyl-6,14 .· · · dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
in the form of bases or of acid-addition salts.
[PREPARATION] [Nature of the strain]
The strain described in FR 2 126 108 deposited at the Northem Régional Research Laboratory (NRRL) under the number NRRL 3892 may be used.
The strain named Allokutzneria albata deposited at the Deutsche Sammlung Von Mikroorganismen und Zellkulturen GmbH (DSMZ) by the group Sanofî-Aventis (Sanofi Aventis Deutschland GmbH, Industriepark HOchst H831, 65926 Frankfurt am Main) under the identification référencé ST108942 may also be used.
[Fermentation and purification to isolate sequanamycln of formula (A)]
The fermentation and purification process described in FR 2 126 108 makes it possible to isolate sequanamycin of formula (A) from the strain Allokutzneria albata. This may be performed by application of the protocol below. This protocol is given as a nonlimiting illustration: it may be adapted to other conditions.
Thus, the fermentation process described below was performed for 500 litres, but may be adapted for smaller or larger proportions.
The preculture medium (named medium 5294) used is typically the following:
| Component | g/L |
| Glucose | 4 |
| Yeast extract | 4 |
| Malt extract | 10 |
| CaCOs | 2 |
The pH of the medium before sterilization is 7.2.
.♦ ·»
The main culture medium (named medium 5254-SeqO1) used is typically the following:
| Component | g/L |
| Glucose | 15 |
| Soybean mea! | 10 |
| Corn macération water | 3 |
| CaCOa | 1 |
| NaCI | 5 |
The fermentation process is typicaliy as follows:
vial from the Banque de Cellules de Travail (BCT)
I
Step 1: Preculture 1
500 pL of BCT were placed in a 300 m! conical flask comprising twice 100 ml of medium 5294. The mixture was stirred for 96 hours at 28’C.
I
Step 2: Preculture 2 ml of the culture medium from step 1 were placed in 4 times 500 ml of medium 5294 in a 2-litre conical flask, and the mixture was then stirred for 72 hours at 28’C.
I
Step 3: Preculture 3
1.5 L of the culture medium from step 2 were placed in 30 litres of medium 5294 in a 42litre bioreactor, and the mixture was then stirred and aerated for 24 hours at 28‘C, without monitoring the pH.
I
Step 4 (main culturing):
kg of the culture medium from step 3 were placed in 500 litres of medium 5294-Seq1 in an 800-litre bioreactor, and the mixture was then stirred and aerated for 96±5 hours at 28’C, without monitoring the pH.
I
Harvesting .· · ·
The fermentation process described above was performed for 500 litres, but may be adapted for smaller or larger proportions. It was performed, for example, at a scale of 7000 litres as follows, using the same culture media: Preculture 1 = 250 ml, inoculum: one vial of BOT.
Preculture 2 = 5 litres in flasks (2 χ 2.5 litres), inoculum of 0.5% from preculture 1. Preculture 3 = 400 litres of medium in a 600 litre bioreactor, seeding rate of 1.25% from preculture 2.
Main culture = 7000 litres of medium in a 10 000 litre bioreactor, seeding rate of 5.7% from preculture 3.
The fermentation process is followed by the purification process below (performed on the 500 litre fermentation broth described above).
Once the fermentation was complété, the fermentation broth was separated into culture supematant and mycélium using a cylindrical seed grader. The séparation led to about 440 litres of culture supematant.
In separate batches, 100-120 litres of culture supematant comprising, inter alia, the macrolide (sequanamycin (A)) were placed on a column filled with adsorption resin (glass column filled with styrene-divinylbenzene copolymer, inside diameter of 200, length of about 180 mm, flow rate of 250 ml/min). The resin was then washed with 30%
2-propanol.
The sequanamycin (A) was isolated by eluting the column with the following elution gradient: 30-70% B over 45 minutes, 70% B over 10 minutes, 100% B over 25 min; with A = Η2θ, B = 2-propanol, modifier 1 vol% NhUAc 50 g/L adjusted to pH 7).
The fractions comprising the sequanamycin (A) were combined and the 2-propanol was evaporated off. The pH of the solution obtained was adjusted to above 7.5 and the solution was then extracted twice with EtOAc. The organic phases were combined and the solvents were evaporated off. The oil obtained (about 10 g per 100 litres of culture supematant) was purified on silica gel (column of 40 mm χ 260 mm), the column being eluted with an n-heptane to 30/70 n-heptane/EtOAc gradient over 45 minutes, followed by 30/70 π-heptane/EtOAc maintained for about 40 minutes (with a flow of 100 ml/minute). The monitoring of the purification may be performed by thin-layer chromatography, eluting with EtOAc and revealing the sequanamycins (in the form of blue spots) with a reagent such as vanillin.
.* ··
According to the concentration of sequanamycin (A) in the individual 100 litre batches, about 2.5 to 3.5 g of sequanamycin (A) with a purity of 68-75% (determined by NMR) were obtained per batch.
If a higher purity is required, the sequanamycin (A) obtained may be repurified by reverse-phase chromatography on a WatersAtlantis machine with a 50* 100 mm, 5 μ column. An elution gradient of H2O (A) and acetonitrile (B) and 1 vol% NH4AC 50 g/L adjusted to pH 7 was used (40-60% B over 30 minutes, flow rate of 140 ml/min). The chromatography was monitored by a light-scattering electrical signal. The fractions comprising the sequanamycin (A) were combined and lyophilized after having evaporated off the acetonitrile. The sequanamycin (A) yield after this final purification step was 57%, with an 85% pure compound according to the NMR analyses.
The compounds of formula (I) according to the invention are prepared from sequanamycin of formula (A).
[Processes for preparing the compounds of formula (I) from sequanamycin of formula (A)]
In the steps described below, the usual organic chemistry reactions may be followed, especially those described in Compréhensive Organic Transformations: A Guide to Functional Group Préparations by Richard C. Larock, published by John Wiley & Sons Inc.
In the text hereinbelow, the term protecting group PG means a group that can, firstly, p rote et a reactive fonction such as a hydroxyl or an amine during the synthesis and, secondly, regenerate the Intact reactive fonction at the end of the synthesis. Examples of protecting groups and also protection and deprotection methods are given In Protective Groups in Organic Synthesis, Greene et al., 4th Edition (John Wiley & Sons, Inc., New York), 2007.
In the text hereinbelow, the term leaving group LG means a group that can be readily cleaved from a molécule by breaking a heterolytic bond, with loss of an électron pair. This group may thus be readily replaced with another group, for example during a substitution reaction. Such leaving groups are, for example, halogens or an activated hydroxyl group such as a methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups and also référencés for their préparation are given in
Advanced Organic Chemistry, M.B. Smith and J. March, 6th Edition, Wiley Interscience, 2007, pp. 496-501.
In accordance with the invention, the compounds of formula (I) in which Y represents a group -(C=O)-NR2R3 may be prepared according to the process characterized in that:
a compound of formula (I), in which Y represents a hydrogen atom below:
O
and R1 and Z are as defined for the compounds of formula (I), is reacted with a compound of formula (II) HNR2R3 in which R2 and R3 are as defined for the compounds of formula (I), in the presence of a carbonyl dérivative and a base.
The introduction of a group Y representing a group -(C=O)-NR2R3 into the compounds of formula (IB) typically comprises the following four successive steps:
• a-1 ) protection of the hydroxyl fonctions of the compound of formula (IB), • a-2) formation of a carbonyl intermediate from the hydroxyl fonction in position 7 of the macrocycle, • a-3) reaction of the carbonyl intermediate with a compound of formula (II) HNR2R3.
• a-4) deprotection of the hydroxyl fonctions.
In step a-1), the hydroxyl fonctions of the compound of formula (IB) are protected to form a compound of formula (lll) below, the hydroxyl fonction in position 7 of the macrocycle (onto which the group Y will be introduced) remaining free:
OU)
In which:
• Ri and Z are as defined for the compounds of formula (I);
• PGi and PG2 independentiy represent a hydroxyl-function protecting group.
In step a-2), the hydroxyl fonction in position 7 of the macrocycle of the compound of formula (III) is used to form a carbonyl intermediate of formula (IV) below:
in which:
· Ri and Z are as defined for the compounds of formula (I);
• LG represents a leaving group;
• PGt and PG2 independentiy represent a hydroxyl-function protecting group.
In step a-3), the carbonyl intermediate of formula (IV) is reacted with a compound of formula (II) HNR2R3 in which R2 and R3 are as defined for the compounds of formula (I).
Step a-3) is typically performed in a polar solvent, for instance dimethylformamide (DMF), generally for 10 to 48 hours and at room température.
In step a-4), the hydroxyl fonctions of the compound obtained in step a-3) are deprotected.
Step a-4) is typically performed according to the deprotection processes described in Protective Groups in Organic Chemistry, J.F.W. McOmie, Plénum Press, 1973 or in Greene's Protective Groups in Organic Synthesis, by Theodora W. Greene published by John Wiley & Sons Inc., 2006.
As regards step a-1), the hydroxyl fonctions of compound (IB) are protected, for example, with acetate fonctions. This protection réaction may be performed by placing the compound of formula (IB) in contact with acetic anhydride in the presence of a base, especially a nitrogenous base, for example pyridine, at room température, the hydroxyl fonction in position 7 of the macrocycle onto which the group Y will be introduced remaining free, to form a compound of formula (Ilia) below:
O
Z' in which:
• Ri and Z are as defined for the compounds of formula (I).
In a first embodiment of step a-2), a compound of formula (lll) as defined above is reacted, for example, with 4-N,N-dimethylaminopyridine (DMAP) and trichloromethyl chloroformate, generally in the presence of a base, especially a nitrogenous base, for • » example pyridine, in an apolar aprotic solvent, for example dichloromethane, at a température between -20°C and room température and for a time of between 5 and 30 hours, to form two carbonyl intermediates of formulae (IVa) and (IVp) below:
in which:
• Ri and Z are as defined for the compounds of formula (I);
• PGt and PGî independently represent a hydroxyl-function protecting group; or
in which:
• Ri and Z are as defined for the compounds of formula (I);
• PGi and PG2 independently represent a hydroxyl-function protecting group, for example an acetate fonction.
In a second embodiment of step a-2), a compound of formula (III) is reacted, for example, with Imidazole and diphosgene to form a carbonyl Intermediate of formula (IVy) below:
In which:
• Rt and Z are as defined for the compounds of formula (I);
• PGi and PG2 independentiy represent a hydroxyl-function protecting group, for example an acetate fonction.
In a third embodiment of step a-2), a compound of formula (III) is reacted, for example, with diphosgene to form a carbonyl intermediate of formula (IV8) below:
in which:
* · • Ri and Z are as defined for the compounds of formula (I);
• PGi and PG2 independently represent a hydroxyl-function protecting group, for example an acetate fonction.
In particular, steps a-1), a-2), a-3) and a-4) may be performed simultaneously or in reverse order. Thus, for example:
a-1) the hydroxyl fonctions of the compound of formula (IB) are protected, and a carbonyî intermediate is formed from the hydroxyl fonction in position 7 of the macrocycle by microwave heating of the compound of formula (IB) with, for example, 10 Ν,Ν'-carbonyldiimidazole, in a solvent, for instance cyclohexane, and at a température of between 80’C and 100’C, to obtain a compound of formula:
in which Z and Ri are as defined for a compound of formula (I);
a'-2) the hydroxyl fonctions are deprotected by placing the compound of formula (XX) In contact with an acid, for instance hydrochloric acid, in a solvent, for instance tetrahydrofuran, to obtain a compound of formula:
(XXI) in which Z and Ri are as defined for a compound of formula (I);
a'-3), the compound of formula (XXI) Is reacted with a compound of formula (II) HNR2R3 in which R2 and R3 are as defined for the compounds of formula (I).
Step a'-3) is typically performed in a polar solvent, for instance dimethylformamide (DMF), in the presence of a base, for instance 1,8-diazabicyclo[5.4.0]undec-7-ene, generally for 10 to 48 hours and at room température.
In accordance with the invention, the compounds of formula (I) in which Y represents a group -ÎC=O)-NR2R3 may also be prepared according to the process characterized in that:
b-1) a compound of formula (V):
O
in which:
.· · » • Ri, R2 and R3 are as defined for the compounds of formula (I);
is reacted with an oxidizing agent to obtain a compound of formula (VI):
In which:
Ri, R2 and R3 are as defined for the compounds of formula (I);
b-2) the compound of formula (VI) thus obtained is reacted with a compound of formula (VII):
ZNH2 (VII) in which Z is as defined for compound (I), in the presence of a reducing agent, to obtain the expected compound of formula (I).
In step b-1), the oxidation of the compound of formula (V) is performed via the action of an oxidizing agent, for instance sodium periodate, in a polar solvent, for instance MeOH, and at a température of between 0 and 10°C.
In step b-2), the reaction of the compound of formula (VI) with a compound of formula (VII) takes place in the presence of a reducing agent, for instance sodium cyanoborohydride, in a slightly acldic medium, in a solvent such as MeOH.
In accordance with the invention, the compounds of formula (I) In which Y represents a hydrogen atom may be prepared according to the process characterized in that:
· c-1) a compound of formula (VIII):
O
in which:
• Ri is as defined for the compounds of formula (I);
is reacted with an oxidizing agent to obtain a compound of formula (IX):
O
Y in which Ri is as defined for the compounds of formula (1);
c-2) the compound of formula (IX) thus obtained is reacted with a compound of formula (VII):
ZNH2 (VII) in which Z is as defined for compound (I), in the presence of a reducing agent, to obtain the expected compound of formula (I).
Steps o-1) and c-2) are performed under the same operating conditions as those described in steps b-1) and b-2) above.
.· ··
In accordance with the invention, the compounds of formula (I) in which Y represents a group -<C=O)-O-Ri8 may be prepared according to the process characterized in that:
a compound of formula (XXI):
in which Z and Ri are as defined for a compound of formula (I), is reacted with an alcohol of formula HO-Rie (XXII), in the presence of a base.
The reaction is performed in the presence of a minerai base, for instance potassium carbonate, at room température.
In particular, certain compounds of formula (I) may be prepared from other compounds of formula (I). Thus, for example, a compound of formula (I) in which Z = Me may be prepared from a compound of formula (I) in which Z - H, by reaction with formaldéhyde in the presence of formic acid and In a solvent, for instance chloroform.
The compounds of formula (I) thus obtained may be subsequently separated from the reaction medium and purified according to standard methods, for example by crystallization or chromatography.
The compounds of formula (I) thus obtained are isolated in the form of the free base or of a sait, according to the standard techniques.
The compounds of formula (II) are commercial, known or prepared according to methods known to those skilled in the art.
The compounds of formula (V) in which Y represents a group -(C=O)NR2R3 are prepared by reacting a compound of formula (VIII):
in which Ri is as defîned for the compounds of formula (I);
with a compound of formula (II) HNR2R3 in which R2 and R3 are as defîned for the compounds of formula (I), in the presence of a carbonyl dérivative, according to the four steps below:
• d-1 ) protection of the hydroxyl fonctions of the compound of formula (VIII), · d-2) formation of an activated intermediate by activation of the hydroxyl fonction in position 7 of the macrocycle, • d-3) reaction of the activated intermediate with a compound of formula (II) HNR2R3, • d-4) optional deprotection of the hydroxyl fonctions.
In step d-1), the hydroxyl fonctions of the compound of formula (VIII) are protected to form a compound of formula (X) below (the hydroxyl fonction in position 7 of the macrocycle onto which the group Y will be introduced remaining free):
in which:
• Ri is as defined for the compounds of formula (I);
• PGi, PG2, PG3 and PG4 Independentiy represent a hydroxyl-function protecting group.
In step d-2), a carbonyl intermediate Is formed from the hydroxyl fonction in position 7 of the macrocycle of the compound of formula (X). especially one or more of the carbonyl intermediates of formula (XI) below:
O
in which:
• Ri is as defined for the compounds of formula (I);
• LG represents a leaving group;
PGi, PG2PG3 and PG4 independentiy represent a hydroxyl-function protecting group.
.· »·
In step d-3), the carbonyl intermediate obtained in step d-2) is reacted with a compound of formula (II) HNR2R3 in which R2 and R3 are as defined for the compounds of formula (I).
Step d-3) is typically performed in a polar solvent, for instance dimethylformamide (DMF), generally for 10 to 48 hours and at room température.
In step d-4), the hydroxyl fonctions of the compound obtained in step d-3) are deprotected.
Step d-4) is typically performed according to the deprotection processes described in Protective Groups in Organic Chemistry, J.F.W. McOmie, Plénum Press, 1973 or in Greene's Protective Groups in Organic Synthesis, by Theodora W. Greene published by John Wiley & Sons Inc., 2006.
In a first embodiment of step d-1 ), the hydroxyl fonctions of compound (VIII) are protected, for example, with acetate fonctions. This protection reaction may be performed by placing the compound of formula (VIII) in contact with acetic anhydride in the presence of a base, especially a nitrogenous base, for example pyridine, at a température typically ranging from room température to 160“C, the hydroxyl fonction in position 7 of the macrocycle onto which the group Y will be introduced remaining free, to form a compound of formula (Xa) below:
in which Ri is as defined for the compounds of formula (I).
In a second embodiment, step d-1) typically comprises the following three successive steps d-1-1), d-1-2) and d-1-3):
- step d-1-1) the hydroxyl fonctions of the compound of formula (VIII) are protected 5 with acyl imidazole fonctions to form a compound of formula (XII) by placing compound (VIII) in contact with Ι,Γ-carbonyldiimidazole in an apolar aprotic solvent, for example toluene, for a time from 10 minutes to 3 hours and at a température between room température and 80*C:
in which Ri is as defined for the compounds of formula (I).
The tertiary alcohol of mycarose reacts with the acylimidazole of the secondary alcohol at a to form the carbonate.
- step d-1-2) the hydroxyl fonctions are deprotected by placing the compound of formula (XII) in contact with an acid, generally hydrochloric acid, In a polar aprotic solvent, for example tetrahydrofuran (THF), typically at room température and for a time from 2 to 24 hours, for example, to form the compound of formula (XIII) below:
in which Rt is as defined for the compounds of formula (I).
- step d-1-3) the secondary hydroxyl fonctions of the compound of formula (XIII) are protected with acetate fonctions by placing the said compound in contact with acetic anhydride in the presence of a base, especially a nitrogenous base, for example pyridine, typically at room température and for a time from 5 to 48 hours, for example:
in which Rt is as defined for the compounds of formula (I).
In a first embodiment of step d-2), a compound of formula (Xa) as defined above is reacted with 4-N,N-dimethylaminopyridine (DMAP) and trichloromethyi chloroformate, generally In the presence of a base, especially a nitrogenous base, for example pyridine, In an apolar aprotic solvent, for exampie dichloromethane, at a température between -20*C and 5’C for a time of between 30 minutes and 10 hours, and then at room température for a time of between 5 and 30 hours, to form two carbonyl intermediates of formulae (Xla) and (ΧΙβ) below:
in which Ri is as defined for the compounds of formula (I).
In a second embodiment of step d-2), the compound of formula (XIV) is reacted, for example, with DMAP and trichloromethyl chloroformate, generally in the presence of a base, especially a nitrogenous base, for example pyridine, to form two carbonyl intermediates of formulae (XV) and (XVI) below:
• ·
In a third embodiment of step d-2), a compound of formula (XIV) is reacted, for example, with 1,1-carbonyldiimidazole to form a carbonyl intermediate of formula (XVII) 10 below:
in which Ri is as defined for the compounds of formula (I).
In a fourth embodiment of step d-2), a compound of formula (XIV) is reacted, for example, with diphosgene to form a carbonyl intermediate of formula (XVIII) below:
in which Ri is as defined for the compounds of formula (I).
The compounds of formula (VII) are commerdally available, known or prepared according to methods known to those skilled in the art, and may be in sait form, such as the hydrochloride.
The compounds of formula (VIII) are prepared by reacting the sequanamycins (A) with a compound of formula (XIX) H2NOR1 in which Ri is as defined for the compounds of « » formula (I), in the presence of a base, for instance triethylamine, if necessary. The reaction is performed in a solvent, for Instance methanol.
The compounds of formula (XIX) are commercially available, known or prepared 5 according to methods known to those skilled in the art, and may be in sait form, such as the hydrochloride.
The compounds of formula (XXII) are commercially available, known or prepared according to methods known to those skilled in the art.
According to another of its aspects, a subject of the présent invention is also the compounds of formulae (V) and (VIII). These compounds are useful as intermediates for synthesizing the compounds of formula (I).
Thus, a subject of the invention is compounds of formula (V):
O
in which:
• Ri, R2 and R3 are as defined for the compounds of formula (I).
A subject of the invention is also compounds of formula (VIII): O
in which:
• Ri is as defined for the compounds of formula (I).
[Examples of préparation of the compounds of formula (I) from sequanamycln of formula (A)]
The following Examples describe the préparation of certain compounds in accordance with the invention. These examples are not limiting and merely illustrate the présent invention.
In the Préparations and in the Examples, the following abbreviations are used:
EtOAc: ethyl acetate
TLC: thin-layer chromatography
CHCh: chloroform
DCM: dichloromethane
DMF: N,N-dimethylformamide
TEA: triethylamine
NalCU: sodium metaperiodate, sodium periodate
K2CO3: potassium carbonate
MeOH: methanol
MgSO<: magnésium sulfate
NaBHaCN: sodium cyanoborohydride
NaCl: sodium chloride
NaHCOa: sodium bicarbonate NaîSOj sodium sulfate NH4CI: ammonium chloride NH4AC: ammonium acetate THF: tetrahydrofuran RT: room température
MATERIALS AND METHODS
The progress of the synthetic reactions is monitored by TLC. The plates are made of glass and are coated with Merck 60 F254 silica gel. After elution, the plates are observed under ultraviolet light at 254 nm and then revealed by spraying with a 5M sulfuric acid/water solution followed by heating.
The microwave réactions were performed using a Biotage Initiator 8 EXP microwave machine.
The products were purified, when necessary, on a Biotage SP-1 chromatograph or a Spot 2 chromatograph from Merck. The columns used are Merck 15-40 pm silica columns (2.5 g to 400 g).
Analyses
Mass Spectrometry (MS):
Method a:
• The spectra were acquired on a Waters UPLC-SQD machine;
• Ionization: electrospray in positive and/or négative mode (ES+/-);
• Chromatographie conditions:
• Column: Acquity BEH C18 -1.7 pm - 2.1 x 50 mm, • Solvents: A: H2O (0.1 % formic acid) B: CH3CN (0.1 % formic acid), • Column température: 50eC, • Flow rate: 1 ml/min, • Gradient (2 min): from 5% to 50% B over 0.8 min; 1.2 min: 100% B; 1.85 min: 100% B; 1.95: 5% B.
Method b:
• The spectra were acquired on a Waters UPLC-SQD machine;
• Ionization: electrospray in positive and/or négative mode (ES+/-);
• Chromatographie conditions:
• Column: Acquity BEH C18 -1.7 pm - 2,1 x 50 mm, • Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid), • Column température: 50eC, • Flow rate: 0.8 ml/min, • Gradient (2.5 min): from 5% to 100% B over 1.8 min; 2.40 min: 100% B; 2.45 min: 100% B; from 100% to 5% B over 0.05 min.
Method c:
• The spectra were acquired on a Waters ZQ machine;
• Ionization: electrospray in positive and/or négative mode (ES+/-);
• Chromatographie conditions:
• Column: XBridge C18- 2.5 pm - 3 x 50 mm, « » • Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid), • Column température: 70eC, • Flow rate: 0.9 ml/min, • Gradient (7 min): from 5% to 100% B over 5.3 min; 5.5 min: 100% B; 6.3 min: 5% B.
Method d:
• The spectra were acquired on a Waters UPLC-SQD machine;
• lonization: electrospray in positive and/or négative mode (ES+/-);
• Chromatographie conditions:
• Column: Acquity BEH C18 -1.7 pm - 2.1 x 50 mm, • Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid), • Column température: 50*C, • Flow rate: 1 ml/min, • Gradient (5 min): from 5% to 100% B over 4.2 min; 4.6 min: 100% B; 4.8 min: 5% B.
Method e:
• The spectra were acquired on a Waters ZQ machine;
• lonization: electrospray in positive and/or négative mode (ES+/-);
• Chromatographie conditions:
• Xselect C18 column 3,5 pm - 3 x 50 mm, • Solvents: A: H2O (0.1 % formic acid) B: CH3CN (0.1% formic acid), • Column température: 60eC, • Flow rate: 1 ml/min, • Gradient (7 min): from 10% to 100% B over 4.5 min; 4.85 min: 100% B; 6.5 min: 10% B.
Method f:
• The spectra were acquired on an Agitent 6110 or Shlmadzu 2010 machine;
• lonization: electrospray in positive and/or négative mode (ES+/-);
• Xtimate C18 column 2.1 X30mm, 3pm, • Solvents: A: H2O (4L) + TFA (1.5 mL) B: CH3CN (4L) + TFA (0.75 mL), • Column température: 50°C, a » • Flow rate: 1.2 ml/min, • Gradient (2 min): from 10% to 80% B over 0.9 min; 1.5 min: 80% B; 1.51 min: 10% B; 2 min: 10% B.
Method g:
• The spectra were acquired on a Shimadzu 2010 machine;
• lonization: electrospray in positive and/or négative mode (ES+/-);
• Merck RP-18e 2 X 25 mm column, • Solvents: A: H2O (4L) + TFA (1.5 mL) B: CH3CN (4L) + TFA (0.75 mL), • Column température: 50’C, • Flow rate: 1.0 ml/min from 0 to 0.08 min; 1.5 ml from 0.08 to 1.50 min, • Gradient (1.50 min): from 0 to 0.08 min 5% B; from 5% to 95% B from 0.08 to 0.7 min; 1,10 min: 95% B; 1.11: 5% B; 1.5 min: 5% B.
Method h:
• The spectra were acquired on an Agllent 6110 or Shimadzu 2010 machine;
• lonization: electrospray in positive and/or négative mode (ES+/-);
• XtimateCI 8 column 2.1 X30mm,3pm, • Solvents: A: H2O (4L) + TFA (1.5 mL) B: CH3CN (4L) + TFA (0.75 mL), • Column température: 50'C, • Flow rate: 1.2 ml/min, • Gradient (2 min): from 30% to 90% B over 0.9 min; 1.5 min: 90% B; 1.51 min: 30% B; 2 min: 30% B.
Method I:
• The spectra were acquired on an Agilent 6110 machine;
• lonization: electrospray in positive and/or négative mode (ES+/-);
• Columns A: Durashell C18 2.1 X 30 mm, 3 pm; B: Xbrige RP18 2.1 X 50 mm, 5pm, • Solvents: A: H2O (4L) + TFA (1.5 mL) B: CH3CN (4L) + TFA (0.75 mL), • Column température: 50’C, • Flow rate: 1.2 ml/min, • Gradient (2 min): from 10% to 80% B over 0.9 min; 1.5 min: 80% B; 1.51 min: 10% B; 2 min: 10% B.
1H Nuclear magnetic résonance (NMR)
The 1H NMR spectra were recorded on a Broker Avance spectrometer (300 MHz, 400 MHz, 500 MHz or 600 MHz) in deuterated DMSO. The chemical shifts are expressed in units δ (ppm) using tetramethylsilane (TMS) as internai reference. For the interprétation of the spectra, the following abbreviations were used: s = singlet, d = doublet, t = triplet, q = quartet, quint - quintet, sext = sextet, dd = doubled doublet, ddd = doublet of doubled doublets, m = multiplet, ax. = axial, equat. = équatorial.
PREPARATION
Préparation of the Intermediates for the examples described below:
Préparation 1:
(2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-{[(2R,4R,5S,6S)-4,5-dihydroxy-4,6dimethyltetrahydro-2H-pyran-2-yl]oxy}-7-hydroxy-2-(1-([(2R,3R14R,5R,6R)-5-hydroxy-3,4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-([(2S,3R,6R)-3-hydroxy-
4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy)-3,5,7,9,11,13-hexamethyl-6,14dioxooxacyclotetradecan-4-yl 3-methylbutanoate.
O
HO*ï™eON
....................<0
OH g of sequanamycin (A) are placed in 175 ml of MeOH with stirring, and 5.3 ml of TEA, and 3 g of methylhydroxyiamine hydrochloride are then added, in this order. The stirring is continued at RT for 20 hours and the MeOH Is then evaporated off under vacuum. The crude reaction product is taken up in 150 ml of DCM and washed with 100 ml of water and then with 100 ml of saturated aqueous NaCI solution. The aqueous phases are extracted with 150 ml of DCM. The organic phases are combined, dried over MgSO<, filtered and concentrated under vacuum. 12.7 g of the product obtained are suspended in 70 ml of a petroleum ether (40-60’C)/isopropanol mixture (2/1). The mixture is heated to 70 C, the Insoluble matter is filtered off while hot and the product is then left to precipitate out at RT over 20 hours. It is filtered off by suction and rinsed with 20 ml of a petroleum ether (40-60°C)/isopropanol mixture (2/1). The precipitate is dried under vacuum at 35’C to give 10.62 g of expected product.
MS: method c
Rétention time Tr (min) = 4.87; [M+Na]+: m/z 1014; [M-H+HCO2H]-: m/z 1036.
1H NMR spectrum (500 MHz, in ppm, DMSO-de): 0.81 (d, J=6.8 Hz, 3 H); 0.93 to 1.01 (m, 15 H); 1.07 (d, J =7.0 Hz, 3 H); 1.09 to 1.13 (m, 9 H); 1.17 (d, J=6.0 Hz, 3 H);
1.18 (d, J=6.0 Hz, 3 H); 1.24 (s, 3H); 1.44 (dd, J=10.8 and 14.4 Hz, 1 H); 1.68 to 1.76 (m, 2 H); 1.81 (d, J=14.4 Hz, 1 H); 1.88 (dd, J=11.5 and 15.9 Hz, 1 H); 1.96 to 2.06 (m, 3 H); 2.07 to 2.20 (m, 4 H); 2.73 (quint, J=7.0 Hz, 1 H); 2.81 (t, J=9.0 Hz, 1H); 2.89 to 2.97 (m, 2 H); 3.03 (ddd, J=2.5 and 7.3 and 9.5 Hz, 1 H); 3.18 (q, J=6.8 Hz, 1 H); 3.34 to 3.36 (m, 2 H); 3.37 (s, 3 H); 3.45 (s, 3 H); 3.52 (dq, J=6.2 and 9.4 Hz, 1 H); 3.60 (s, 1 H); 3.62 to 3.65 (m, 1 H); 3.66 (t, J=2.5 Hz, 1 H); 3.71 to 3.77 (m, 1 H); 3.78 (m, 1 H); 3.80 (s, 3 H); 3.81 to 3.84 (m, 1 H); 3.87 (m, 1 H); 4.39 to 4.46 (m, 3 H); 4.50 (s, 1 H); 4.72 (d, J = 8.3 Hz, 1 H); 4.78 (d, J=8.3 Hz, 1 H); 4.84 (d, J=7.3 Hz, 1 H); 4.87 (d, J=3.8 Hz, 1 H);
5.19 (d, J=4.4 Hz, 1 H).
Préparation 2: benzyl carbamate (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12([(2R,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-2-(1{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy)propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2Hpyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl
3-methylbutanoate.
Préparation 2.1:
ο
8.6 g of the compound obtained in Préparation 1 are placed in 86 ml of pyridine, and 8.27 ml of acetic anhydride are added. The mixture is stirred for 24 hours at room température, and the pyridine is then concentrated under vacuum. 150 ml of DCM are added and the resulting mixture is washed with 120 ml of 1N HCl solution and then with 100 ml of saturated aqueous NaCI solution. The aqueous phases are extracted with 150 ml of DCM. The organic phases are combined, dried over NaîSOi, filtered and then evaporated to dryness. 9.75 g of the expected product are obtained.
MS: method a
Rétention time Tr (min) = 1.27; [M+Na]+: m/z 1140.
1H NMR spectrum (400 MHz, in ppm, DMSO*dg): 0.81 (d, J =6.8 Hz, 3 H); 0.91 to 1.01 (m, 15 H); 1.02 (s, 3 H); 1.03 to 1.12 (m, 12 H); 1.21 (d, J=6.1 Hz, 3 H); 1.24 (s, 3 H);
1.50 (dd, J=10.5 and 14.5 Hz, 1H); 1.72 to 1.94 (m, 6 H); 1.96 to 2.10 (m, 8 H); 2.12 to
2.18 (m, 3 H); 2.22 (s, 3 H); 2.77 (m, 1 H); 3.02 (dd, J=2.7 and 8.1 Hz, 1 H); 3.08 (m, 1 H);
3.16 (q, J=7.1 Hz, 1 H); 3.36 (m, 1 H); 3.39 (s, 3 H); 3.41 (s, 3H); 3.45 (m, 1 H); 3.63 to
3.72 (m, 2 H); 3.76 (broad s, 4 H); 3.80 (m, 1 H); 3.85 (t, J=2.7 Hz, 1 H); 4.11 (m, 1 H);
4.17 (s, 1 H); 4.35 (dd, J=2.7 and 10.3 Hz, 1 H); 4.42 (m, 2 H); 4.52 (d, J=8.1 Hz, 1 H);
4.63 (d, J=7.3 Hz, 1 H); 4.69 (d, J=9.0 Hz, 1 H); 4.75 (d, J=9.0 Hz, 1 H); 4.93 (d, J = 4.0 Hz, 1 H); 5.00 (d, J=7.3 Hz, 1 H).
• »
Préparation 2.2:
g of the compound obtained in Préparation 2.1 are placed in 20 ml of pyridine in a microwave reactor, and 1 ml of acetic anhydride and 50 mg of 4-dimethylaminopyridine are added. The solution is heated for 2 hours at 155°C by microwave. The reaction medium is poured into 50 ml of DCM and washed with 30 ml of 1N HCl solution and then with 30 ml of water. The aqueous phases are extracted with twice 50 ml of DCM. The organic phases are combined, dried over NaîSO*. filtered and then evaporated to dryness under vacuum. The residue, 1.1 g of a brown foam, is purified by chromatography on a Merck cartridge (50 g of 15-40 pm silica), eluting with a 40/60 EtOAc/heptane mixture. 0.69 g of the expected compound is obtained.
MS: method a
Rétention time Tr (min) = 1.29; [M+Na]+: m/z 1182.
1H NMR spectrum (500 MHz, In ppm, DMSO-de): 0.81 (d, J=6.9 Hz, 3 H); 0.91 to 1.02 (m, 18 H); 1.06 (m, 6 H); 1.10 (d, J=6.9 Hz, 3 H); 1.19 to 1.26 (m, 6 H); 1.35 (s, 3 H);
1.44 (dd, J=10.5 and 14.5 Hz, 1H); 1.79 (m, 1 H); 1.84 to 2.09 (m, 15 H); 2.11 to 2.18 (m, 6 H); 2.73 (m, 1 H); 3.02 (dd, J=2.7 and 7.8 Hz,1 H); 3.06 to 3.20 (m, 3 H); 3.35 to 3.42 (m, 8 H); 3.60 to 3.69 (m, 2 H); 3.77 (broad s, 4 H); 3.80 (m, 1 H); 3.85 (t, J=2.7 Hz, 1 H); 4.16 (m, 1 H); 4.36 (dd, J=2.7 and 9.9 Hz, 1 H); 4.48 to 4.53 (m, 3 H); 4.59 (d, J = 7.1 Hz, 1 H); 4.73 to 4.80 (m, 2 H); 4.87 (d, J=4.3 Hz, 1 H); 5.00 (d, J=7.1 Hz, 1 H).
* ·
Préparation 2.3:
<23*> (2.3.b)
3.5 g ofthe compound obtained in Préparation 2.2 dissolved in 140 ml of DCM and
3.6 m! of pyridine are placed under argon with stirring. The yellow solution obtained is cooled to -10’C, followed by rapid addition of trichloromethy! chloroformate (diphosgene), and stirring is continued at -10°C for 3 hours. 0.368 g of 4-dimethylaminopyridine dissolved In 10 m! of DCM is then added. The reaction medium is maintained at -5’C for a further 30 minutes and is then allowed to warm to room température, and stirring is continued for 20 hours. The solvent is evaporated off and 150 ml of EtOAc are added to the crude reaction product. The mixture Is stirred for 15 minutes at room température and the precipitate formed is then filtered off. It is rinsed with 70 m! of EtOAc and the filtrate is evaporated to dryness under vacuum. 3.92 g of a mixture of the expected compounds (structures 2.3.a and 2.3.b) are obtained. The mixture is used as obtained for the following stage.
Préparation 2.4:
a) Condensation of the amine (benzylamine)
1.5 g ofthe compound obtained in Préparation 2.3 are placed in 30 ml of DMF in a 100 m! round-bottomed flask, and 0.61 ml of benzylamine are then added. The mixture is stirred for 24 hours at room température, followed by addition of 100 g of Ice and 100 ml of water. The precipitate formed is filtered off by suction and washed with a minimum amount of water. After drying in an oven under vacuum at 35’C, 1.18 g of the expected compound are obtained.
b) De protection
1.18 g of the compound obtained in the preceding step are placed In 20 ml of MeOH, and 0.63 g of K2CO3 is added. The heterogeneous medium is stirred at room « « température for 3 hours and then filtered through a No. 4 sinter funnel. The filtrate is taken up in 100 ml of EtOAc and washed with saturated aqueous NaCI solution. The organic phase is dried over MgSO.«, filtered and then evaporated to dryness. 1.05 g of crude compound are obtained, which product is purified by chromatography on a Merck column (30 g of 15-40 pm silica) with a 30/70 to 60/40 EtOAc/heptane elution gradient. 0.466 g of the expected product is obtained.
MS: method c
Rétention time Tr (min) - 5.21; [M+H]+: m/z 1125; base peak: m/z 981 [MH+HCO2H]-: m/z 1169.
1H NMR spectrum (500 MHz, In ppm, DMSO-de): 0.80 (d, /=6.8 Hz, 3 H); 0.92 (d, /=6.8 Hz, 3 H); 0.96 to 1.02 (m, 9 H); 1.05 (m, 6 H); 1.08 to 1.15 (m, 9 H);
1.18 (m, 6 H); 1.67 to 2.18 (m, 10 H); 1.73 (s, 3 H); 2.18 (d, /=6.8 Hz, 2 H); 2.59 to
2.67 (m, 1 H); 2.80 (t, /=8.8 Hz, 1 H); 2.92 (dd, /=2.7 and 8.1 Hz, 1 H); 2.94 to 3.06 (m, 3 H); 3.27 to 3.35 (partially masked m, 1 H); 3.38 (s, 3 H); 3.41 (d, /=9.8 Hz, 1 H); 3.45 (s, 3 H); 3.49 to 3.56 (m, 1 H); 3.60 to 3.72 (m, 4 H); 3.80 (s, 3 H); 3.82 (m, 1 H); 3.87 (broad d, /=5.4 Hz, 1 H); 4.01 to 4.17 (m, 3 H); 4.34 to 4.39 (m, 2 H); 4.45 (d, /=7.8 Hz, 1 H);
4.50 to 4.57 (m, 2 H); 4.85 (d, /=7.3 Hz, 1 H); 4.93 (d, /=2.4 Hz, 1 H); 5.13 (broad s, 1 H);
7.18 to 7.36 (m, 6H).
Préparation 3:
• ·
11.1 g of the compound prepared in Préparation 1 are placed in 220 ml of toluene. 9.07 g of 1,T-carbonyldiimidazole are added and the réaction medium is then heated at 60°C for 45 minutes. It is allowed to cool to room température and the precipitate is filtered off and washed with toluene. The toluene phase is washed with 100 ml of water and then dried over MgSO«. After filtration, the solvent is evaporated off to dryness and 14.26 g of the expected product are recovered.
MS: method a
Rétention time Tr (min) = 1.22; IM+HJ+: m/z 1206; [M-H+HCOOH]-: m/z 1250.
1H NMR spectrum (500 MHz, in ppm, DMSO-de): 0.80 (d, J=6.8 Hz, 3 H);
0.83 (d, J=7.3 Hz, 3 H); 0.90 (d, J=6.8 Hz, 3 H); 0.98 (dt, J=3.2 and 6.4 Hz, 9 H); 1.03 (d. J = 7.3 Hz, 3 H); 1.13 (d, J=6.8 Hz, 3 H); 1.16 (d, J=6.4 Hz, 3 H); 1.24 (t, J=2.9 Hz, 6 H);
I. 29 (d, J=5.9 Hz, 3 H); 1.53 (m, 4 H); 1.78 (m, 1 H); 1.84 to 1.91 (m, 1 H); 1.98 (m, 1 H); 2.02 to 2.11 (m, 3 H); 2.16 (m, 3 H); 2.21 (m, 1 H); 2.34 (dd, J=5.9 and 14.2 Hz,1 H);
2.73 (dq, J=7.2 and 7.3 Hz. 1 H); 3.08 to 3.17 (m, 3 H); 3.38 (m, 1 H); 3.41 (s, 3 H);
3.44 (s, 3 H); 3.56 (d, J=5.9 Hz, 1 H); 3.66 to 3.74 (m, 5 H); 3.78 (ddd, J=2.9 and 6.0 and
II. 6 Hz, 1 H); 3.96 (m, 1 H); 4.07 to 4.20 (m, 3 H); 4.39 (s, 1 H); 4.58 (m, 2 H); 4.63 (d, J=9.3 Hz, 1 H); 4.76 (d, J=9.8 Hz, 1 H); 4.91 (s, 2 H); 5.22 (d, J=6.8 Hz, 1 H); 7.12 (d, J=10.3 Hz, 2 H); 7.61 (d, J=1.5 Hz, 2 H); 8.29 (d, J=8.8 Hz, 2 H).
• *
Préparation 3.2:
ο
14.01 g ofthe compound obtained in Préparation 3.1 are placed in 140 ml ofTHF,
34.8 ml of 1N HCl solution are added and stirring is continued for 24 hours at room température. The reaction medium is poured into 200 ml of DCM and washed with 100 ml of water and then with 100 ml of saturated aqueous sodium bicarbonate solution. The aqueous phases are extracted with 200 ml of DCM, and the organic phases are combined, dried over Na2SO4, filtered and then evaporated to dryness under vacuum. 11.48 g of the expected product are obtained.
MS: method a
Rétention time Tr (min) = 1.19; [M+Na]+: m/z 1040; [M-H + HCOOHJ-: m/z 1062.
1H NMR spectrum (400 MHz, In ppm, DMSO-dt): 0.80 (d, J = 6.8 Hz, 3 H); 0.95 (m, 15 H); 1.03 to 1.17 (m, 12 H); 1.23 (s, 3 H); 1.30 (d, J = 5.9 Hz, 3 H); 1.45 (m, 1 H); 1.52 (s, 3 H); 1.78 to 1.89 (m, 2 H); 1.90 to 2.24 (m, 8 H); 2.37 (dd, J = 5.1 and
13.9 Hz, 1 H); 2.79 (m, 2 H); 2.91 (m, 1 H); 3.03 (ddd, J = 2.7 and 6.8 and 9.5 Hz, 1 H);
3.13 (q, J = 6.7 Hz, 1 H); 3.32 (masked m, 1 H); 3.37 (s, 3 H); 3.45 (s, 3 H); 3.52 (m, 2 H);
3.63 to 3.72 (m, 3 H); 3.80 (s, 3 H); 3.92 (t, J = 3.9 Hz, 1 H); 4.00 (ddd, J = 3.2 and
6.1 and 11.7 Hz, 1 H); 4.08 (m, 1 H); 4.15 (m, 1 H); 4.34 (s, 1 H); 4.45 (d, J = 8.1 Hz, 1 H);
4.63 (d, J = 9.8 Hz, 1 H); 4.68 (d, J=4.2 Hz, 1 H); 4.76 (d, J=9.5 Hz, 1 H); 4.83 (d, J =
7.1 Hz, 1 H); 4.98 (dd, J = 5.1 and 9.0 Hz, 1 H); 5.43 (d, J = 3.9 Hz, 1 H).
Préparation 3.3:
11.4 g of the compound obtained in Préparation 3.2 are placed in 114 ml of pyridine, and 7.4 ml of acetic anhydride are then added. The réaction medium is stirred at room température for 24 hours. The pyridine is evaporated off under vacuum and 200 mi of DCM are added to the crude reaction mixture. The resulting mixture is washed with 150 ml of 1N HCl solution and then with 150 mi of water. The aqueous phases are extracted with twice 200 ml of DCM, and the organic phases are combined, dried over Na2SO4, filtered and then evaporated to dryness under vacuum. 12.2 g of compound are obtained, which product is purified by chromatography on a Merck column (400 g of 1540 pm silica), eluting with a 45/55 EtOAc/heptane mixture. 8.6 g of the expected product are recovered.
MS: method a
Rétention time Tr (min) = 1.29;
[M+H]+: m/z 1102; [M-H+HCOOH]-: m/z 1146.
1H NMR spectrum (400 MHz, in ppm, DMSO-de): 0.81 (d, J=7.3 Hz, 3 H); 0.95 (m, 15 H); 1.06 (m, 6 H); 1.11 (d, J=6.6 Hz, 3 H); 1.20 (d, J=6.1 Hz, 3 H); 1.24 (s, 3 H); 1.29 (d, J=3.9 Hz, 3 H); 1.41 to 1.54 (m, 4H); 1.77 to 1.91 (m, 2 H); 1.96 to 2.09 (m, 10 H); 2.11 to 2.23 (m, 4 H); 2.36 (m, 1 H); 2.79 (m, 1 H); 3.02 (m, 2 H); 3.13 (m, 1 H);
3.35 (m, 1 H); 3.38 (s, 3 H); 3.41 (s, 3 H); 3.52 (d, J=7.1 Hz, 1 H); 3.64 to 3.73 (m, 2 H);
3.74 to 3.83 (m, 5 H); 3.86 (broad s, 1 H); 4.06 to 4.14 (m, 2 H); 4.33 to 4.40 (m, 2 H);
4.52 (d, J=8.1 Hz, 1 H); 4.65 (d, J=9.8 Hz, 1 H); 4.76 (m, 2 H); 4.97 (dd, J=5.3 and 8.9 Hz, 1 H); 5.02 (d, J=6.1 Hz, 1 H).
• ·
Préparation 3.4:
(3 4.8) (3 4 fa) g of the compound obtained in Préparation 3.3 are piaced, under argon, in 190 ml of DCM, and 4.12 m! of pyridine are added. The solution is cooled to -20’C, followed by addition, In a single portion, of 0.8 ml diphosgene, and stirring Is continued at -20’C for 3 hours. 0.443 g of 4-dimethylaminopyridine is added, while still at -20’C, the mixture is then allowed to warm to room température and stirring is continued for 20 hours. The DCM is evaporated off under vacuum and the crude reaction product is taken up in 150 ml of EtOAc and stirred for 1 hour at room température. The precipitate formed is fîltered off and rinsed with 80 ml of EtOAc. The filtrate is evaporated to dryness under vacuum, 4.7 g of the expected compounds (structures 3.4.a and 3.4.b) are obtained as a mixture, and the mixture is used as obtained for the following stage.
MS: method a
Rétention tlme 3.4.a: Tr (min) = 1.1 [M+HJ+: 1251; 3.4.b: Tr (min) = 1.3 [M+Na]+: 1187.
Préparation 3.5:
• ·
a) Condensation of the amine A.
0.64 g of the mixture of compounds obtained in Préparation 3.4 is dissolved in 16 ml of DMF, followed by addition of 401 mg of N-(2-amino-2-methylpropyl)-5-nitro-1Hpyrazole-4-sulfonamide dihydrochloride (prepared according to the process described in International patent application WO 2009/29439 A1) and 374 μ! of TEA. The mixture is stirred for 4 days at room température, and 75 ml of EtOAc are then added. The mixture is washed with 50 ml of water and then with 50 ml of saturated aqueous NaCI solution. The organic phase is dried over MgSOx, filtered and concentrated under reduced pressure. 0.7 g of compound is obtained, which product is purified by chromatography on a silica column (Merck, 30 g of 15-40 pm silica), eluting with a 60/40 heptane/EtOAc mixture.
147 mg of the expected compound are obtained.
b) Deprotection
140 mg of the compound obtained in the preceding step are placed in 3 ml of MeOH. 70 mg of K2CO3 are added to the solution obtained. The mixture is stirred for 24 hours at room température. 15 ml of EtOAc are then added. The mixture is washed with 10 ml of water and then with 10 ml of saturated aqueous NaCI solution. The organic phase is dried over MgSOx, filtered and then evaporated to dryness under vacuum. 0.114 g of the expected product is obtained.
MS: method b
ES*: m/z 1137 (base peak)
1H NMR spectrum (500 MHz, in ppm, DMSO-d«): 0.79 (d, J=6.8 Hz, 3 H);
0.93 (m, 9 H); 1.01 (d, J=6.8 Hz, 3 H); 1.10 (m, 18 H); 1.17 (m, 9 H); 1.64 (s, 3 H); 1.80 (m, 5 H); 1.99 (m, 4 H); 2.13 (m, 3 H); 2.65 (m.1 H); 2.82 (m, 2 H); 2.96 (m, 5 H); 3.30 (masked m, 1 H); 3.37 (s, 3 H); 3.40 (d, J=9.8 Hz, 1 H); 3.46 (s, 3H); 3.51 (m, 1 H); 3.60 (m, 2 H); 3.67 (m, 2 H); 3.78 (m, 1 H); 3.80 (s, 3 H); 3.85 (m. 1 H); 4.08 (broad s, 1H);
4.36 (m, 2 H); 4.44 (d. J=8.3 Hz, 1 H); 4.56 (m, 2 H); 4.80 (d, J=6.4 Hz, 1 H); 4.99 (broad d, J=2.0 Hz, 1H); 5.09 (d, J=3.9 Hz. 1 H); 6.33 (s, 1 H); 6.86 (m, 1 H); 8.07 (broad s, 1 H);
14.52 (m, 1 H).
• «
Préparation 4:
a) Condensation of the amine B
0.64 g of the mixture of compounds obtained in Préparation 3.4 is placed in 15 ml of DMF. 462 mg of N-(2-amino-2-propylmethyl)-2-nitrobenzenesulfonamide hydrochloride (prepared according to the process described in Tetrahedron Letters, 2009, vol. 50, 28, pp. 4050 - 4053) and then 249 μΙ of TEA are added to the solution obtained. The mixture is stirred for 3 days at room température, and 75 ml of EtOAc are then added. The mixture is washed with 50 ml of water and then with 50 ml of saturated aqueous NaCI solution. The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. 0.57 g of compound is obtained, which product is purified by chromatography on silica (30 g of 15-40 pm silica), eluting with a 55/45 heptane/EtOAc mixture.
0.25 g of the expected compound is obtained.
b) Deprotection
0.24 g of the compound obtained in the preceding step is placed in 4 ml of MeOH. 119 mg of potassium carbonate are added to the solution obtained. The suspension is stirred at room température for 24 hours. 20 ml of EtOAc are added and the mixture is washed with 10 ml of water and then with 20 ml of saturated aqueous NaCI solution. The organic phase is dried over MgSO4| filtered and concentrated under reduced pressure. 0.197 g of the expected product is obtained.
MS: method b
ES*: m/z 1147 (base peak)
1H NMR spectrum (500 MHz, In ppm, DMSO-de): 0.79 (d, J-6.8 Hz, 3 H); 0.90 to 0.95 (m, 9 H); 1.01 (d, J=6.8 Hz, 3 H); 1.04 to 1.14 (m, 18 H); 1.15 to 1.20 (m, 9 H);
1.64 (s, 3 H); 1.67 to 1.88 (m, 5 H); 1.92 to 2.05 (m, 4 H); 2.09 to 2.18 (m, 3 H); 2.65 (m, 1 H); 2.81 (t, J=9.0 Hz, 1 H); 2.89 to 3.12 (m, 6 H); 3.31 (partially masked m, 1 H); 3.37 (s, 3 H); 3.40 (d, J=9.5 Hz, 1 H); 3.45 (s, 3 H); 3.51 (m, 1 H); 3.59 to 3.63 (m, 2 H); 3.65 to • ·
3.71 (m, 2 H); 3.78 (m, 1 H); 3.80 (s, 3 H); 3.85 (dd, J=4.7 and 6.5 Hz, 1 H); 4.07 (broad s, 1 H); 4.36 (d, J=6.5 Hz, 1 H); 4.38 (d, J=8.9 Hz, 1 H); 4.43 (d, J=7.9 Hz, 1 H); 4.52 to 4.61 (m, 2 H); 4.83 (d, J=7.1 Hz, 1 H); 4.99 (broad d, J=2.9 Hz, 1 H); 5.11 (broad d, J=4.7 Hz, 1 H); 6.32 (broad s, 1 H); 7.77 to 8.05 (m, 5 H).
Préparation 5:
400 mg of sequanamycin (A), 180 mg of (R)-5-((4-((aminooxy)methyl)-1H-1,2,3triazol-1-yl)methyl)-3-(3-fluorophenyl)oxazolidin-2-one (prepared according to the process described In Journal of Carbohydrate Chemistry, 2006, vol. 25, pp. 407 - 425) and 10 ml of MeOH are added. The solution obtained is stirred for 5 hours at room température. 20 ml of DCM are added. The mixture is washed with 20 ml of 1 M HCl and then with 20 ml of water. The organic phase is dried over MgSO4, filtered through a sinter funnel and then evaporated to dryness. The product is purified by chromatography on a column of silica (Merck, 15-40 pm, 20 g), eluting with a 95/5 DCM/MeOH mixture. 205 mg of the expected compound are recovered.
MS: method b
ES-: [M-H+HCO2HJ-: m/z 1296.
1H NMR spectrum (400 MHz, In ppm, DMSO-de): 0.81 (d, J=6.8 Hz, 3 H); 0.96 (d, J=6.4 Hz, 9 H): 1.00 (m, 6 H); 1.07 (d, J=7.3 Hz, 3 H); 1.08 to 1.13 (m, 9 H);
1.17 (m, 6 H); 1.24 (s, 3 H); 1.46 (m, 1 H); 1.69 to 1.75 (m, 2 H); 1.79 to 1.91 (m, 2 H); 1.95 to 2.20 (m, 7 H); 2.73 (m, 1 H); 2.81 (m, 1 H); 2.89 to 2.97 (m, 2 H); 3.03 (m, 1 H);
3.19 (broad q, J=6.8 Hz, 1 H); 3.27 to 3.38 (partially masked m, 2 H); 3.37 (s, 3 H);
3.45 (s, 3 H); 3.52 (m, 1 H); 3.60 (broad s, 1 H); 3.62 to 3.68 (m, 2 H); 3.72 (m, 1 H); 3.76 to 3.85 (m, 2 H); 3.86 to 3.94 (m, 2 H); 4.26 (t, J=9.3 Hz, 1 H); 4.38 to 4.46 (m, 3 H);
4.50 (s, 1 H); 4.72 (d, J=8.3 Hz, 1 H); 4.78 (d, J=8.6 Hz, 1 H); 4.82 (m, 3 H); 4.89 (broad d, J=3.8 Hz, 1 H); 5.10 (s, 2 H); 5.12 to 5.20 (m, 2 H); 6.97 (dt, J=2.2 and 8.4 Hz, 1 H); 7.27 (broad d, J=8.4 Hz, 1 H); 7.37 to 7.51 (m, 2 H); 8.22 (s, 1 H).
·
EXAMPLE 1: Compound 1
Compound 1-a: (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-hydroxy-2-(1{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2Hpyran-2-yl]oxy)-3,5,7,9,H,l3-hexamethyl-6,14-dioxo-l2-{[(2S,5R,7R)-2,4,5-trimethyl-l,4oxazepan-7-y!]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate.
Compound 1 -b: (2R,3SI4R,5R.7S.9S, 10S, 11 R, 12S.13R)-7-hydroxy-2-( 1 {[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-yl)-10-([(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2Hpyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-([(2S,5S,7R)-2,4,5-trimethyl-1,4oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate.
HO>
g of the compound of Préparation 1 are placed in 68 ml of MeOH. The réaction medium is cooled in an ice bath to a température of +4’C, followed by dropwise addition of a solution of 3.23 g of sodium periodate in 68 ml of water. The mixture is stirred for 6 hours at room température.
The medium is saturated with NaCi and filtered, and the filtrate is extracted with DCM (3x200 ml). The organic phases are combined, washed with saturated aqueous NaCI solution, dried over MgSCh, filtered and finally concentrated under reduced pressure. The oily residue obtained is dissolved, under argon, in 680 ml of MeOH. The pH is adjusted to 7 by addition of acetic add, followed by addition of 2 M methylamine disolved in 12.1 ml of THF. The pH is maintained at 7 with acetic add. After stirring for 30 minutes at room température, 0.95 g of NaBHaCN is added in a single portion, and the mixture is stirred for a further 16 hours at room température. The reaction medium is filtered and rinsed with MeOH. The filtrate is concentrated under reduced pressure and then taken up in 600 ml of DCM. The resulting mixture is washed with saturated aqueous NaCi solution (3 χ 60 ml). The organic phase is dried over MgSO<, filtered and then evaporated to dryness under vacuum. 3.5 g of product are purified by chromatography on * · a Merck cartridge (150 g of 15-40 pm silica) with a 100/0 to 90/10 DCM/MeOH elution gradient. 530 mg of diastereoisomer 1-a, 380 mg of diastereoisomer 1-b and 661 mg of a mixture of the two isomers are obtained.
Compound 1-a:
MS: method b
Rétention time Tr (min) = 1.26; [M+H]+: m/z 989; [M-H+HCO2H]-: m/z 1033 (base peak).
1H NMR spectrum (500 MHz, in ppm, DMSO-de): 0.79 (d, /=6.8 Hz, 3 H); 0.89 to 1.01 (m, 15 H); 1.03 (d, /=6.8 Hz, 3 H); 1.05 to 1.10 (m, 9 H); 1.11 (d, /=6.1 Hz, 3 H); 1.13 (d, /=6.1 Hz, 3 H); 1.24 (s, 3H); 1.48 (dd, /=11.4 and 14.7 Hz, 1 H); 1.70 to 2.08 (m, 8 H); 2.10 to 2.22 (m, 3 H); 2.18 (broad s, 3 H); 2.36 (m, 1 H); 2.57 (m, 1 H); 2.70 (d, /=13.6 Hz, 1 H); 2.75 (m, 1 H); 2.83 (dd, /=2.9 and 16.6 Hz, 1 H);2.92 (dd, /=2.7 and 8.0 Hz, 1 H); 3.03 (m, 1 H); 3.12 (q, /=6.8 Hz, 1 H); 3.30 (partially masked m, 1H); 3.38 (s, 3 H); 3.45 (s, 3 H); 3.52 (m, 1 H); 3.58 to 3.72 (m, 4 H); 3.80 (s, 3 H); 3.89 (m, 2 H); 4.26 (m, 1 H); 4.31 (s, 1 H); 4.45 (d, /=8.0 Hz, 1 H); 4.65 (broad d, /=9.8 Hz, 1 H); 4.70 (d, /=4.6 Hz, 1 H); 4.74 (d, /=9.6 Hz, 1 H); 4.86 (d, /=7.1 Hz, 1 H); 4.93 (dd, /=3.1 and 9.5 Hz, 1 H); 5.33 (d, /=4.6 Hz, 1 H).
Compound 1-b:
MS: method b
Rétention time Tr (min) = 1.26; [M-H+HCO2H]·: m/z 1033 (base peak).
1H NMR spectrum (500 MHz, in ppm, DMSO-de): 0.82 (d, J=6.8 Hz, 3 H); 0.91 to 1.32 (m, 36 H); 1.44 to 1.51 (m, 1 H); 1.80 to 1.87 (m, 1 H); 1.96 to 2.37 (m, 10 H); 2.76 to 2.80 (m, 2 H); 2.77 (s, 3 H); 2.85 (dd, J=3.1 and 16.8 Hz, 1 H); 2.93 (dd, J=2.7 and 8.0 Hz, 1 H); 3.00 to 3.07 (m, 2 H); 3.12 to 3.18 (m, 1 H); 3.28 (d, J=13.7 Hz, 1 H); 3.31 to
3.36 (m, 1 H); 3.40 (s, 3 H); 3.48 (s, 3 H); 3.51 to 3.58 (m, 2 H); 3.64 to 3.70 (m, 2H); 3.82 (s, 3 H); 3.86 to 3.90 (m, 1 H); 3.94 to 4.02 (m, 2 H); 4.31 to 4.37 (m, 1 H); 4.47 (d, J=7.9 Hz, 1 H);4.66 to 4.77 (m, 3 H); 5.12 (dd, J=5.8 and 8.9 Hz, 1 H).
EXAMPLE 2: Compound 2 (2R,3S,4^5^78,98,108,11R.12S,13R)-2-(1-([(2R,3R,4R,5R,6R)-5-hydroxy-3t4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy)propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-
4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7I9111,13-hexamethyl-6,14dioxo-7-(([2-(pyridin-4-yl)ethyl]carbamoyl)oxy)-12-([(2S,5S,7R)-2,4,5-trimethyl-1,4□xa ze pa n-7-yl]oxy)ox a cyclotetra deçà n-4-yl 3-methylbutanoate;
Step 2.1:
660 mg of the mixture of diastereoisomers prepared in Example 1 are placed in 14.7 ml of pyridine. 631 μΙ of acetic anhydride are added. After stirring for 24 hours at room température, 189 μΙ of acetic anhydride are added and stirring is continued at room température for 24 hours. The solution is concentrated under vacuum and the residue is taken up in 200 ml of DCM. The resulting mixture is washed with 1N HCl solution (3 χ 5 m!) and then with saturated aqueous sodium bicarbonate solution (2*5 ml) and finally with saturated aqueous NaCI solution (3x5 ml). The organic phase is dried over MgSO4, filtered and then evaporated to dryness under vacuum. 756 mg of crude product are obtained, which product is purified by chromatography on a Merck cartridge (15-40 pm silica) with a 100/0 to 95/5 DCM/MeOH elution gradient, 287 mg of diastereoisomer 2.1.a and 266 mg of diastereoisomer 2.1.b are obtained.
Compound 2.1.a:
MS: method b
Rétention time Tr (min) = 1.46; [M+H]*: 1073
1H NMR spectrum (500 MHz, In ppm, DMSO-de): 0.79 (s, 3 H); 0.91 (m, 6 H); 0.97 (m, 9 H); 1.02 (d, J=6.6 Hz, 3 H); 1.07 (m, 12 H); 1.19 (d, J=6.1 Hz, 3 H); 1.24(s,
H); 1.49 (dd, J=11.7 and 14.5 Hz, 1 H); 1.82 (m, 4 H); 1.98 (m, 4 H); 2.05 (s, 3H);
2.08 (s, 3 H); 2.16 (m, 3 H); 2.20 (s, 3 H); 2.44 (dd, J=9.9 and 14.4 Hz, 1 H); 2.64(m,
H); 2.74 (m, 2 H); 3.03 (m, 2 H); 3.12 (q, J=6.7 Hz, 1 H); 3.35 (dd, J=4.9 and 10.1 Hz,
H); 3.39 (s, 3 H); 3.41 (s, 3 H); 3.55 (d. J=8.0 Hz, 1 H); 3.67 (m. 2 H); 3.79 (m, 2 H);
3.78 (s, 3 H); 3.86 (t, J=2.7 Hz, 1 H); 4.14 (m, 1 H); 4.31 (s, 1 H); 4.37 (dd, J=2.5 and
9.9 Hz, 1 H); 4.52 (d, J=8.0 Hz, 1H); 4.65 (d, J=9.8 Hz, 1 H); 4.76 (d, J=9.5 Hz, 1 H);
4.79 (d, J=6.8 Hz, 1 H); 4.88 (dd, J=3.4 and 8.6 Hz, 1H); 5.01 (d, J=6.8 Hz, 1 H).
Compound 2.1 .b:
MS: method b
Rétention time Tr (min) = 1.46; [M+H]*: 1073
1H NMR spectrum (500 MHz, In ppm, in DMSO-d«+ TFA + AcOD) : 0.82 (d,
J=6.8 Hz, 3 H); 0.95 (m, 15 H); 1.06 (m, 9 H); 1.20 (m, 6 H); 1.25 (s, 3 H); 1.30 (d, J=6.9 Hz, 3 H); 1.48 (m, 1 H); 1.84 (m, 1 H); 1.94 to 2.36 (m, 10 H); 2.08 (s, 6 H); 2.75 (m, 1 H); 2.76 (s, 3 H); 3.06 (m, 3 H); 3.15 (q, J=6.5 Hz, 1 H); 3.20 (d, J=13.7 Hz, 1 H);
3.37 (dd, J=4.7 and 9.7 Hz, 1 H); 3.40 (s, 3 H); 3.43 (s, 3 H); 3.54 (m, 1 H); 3.60 (m, 1 H);
3.68 to 3.77 (m. 2 H); 3.81 (m, 1 H); 3.79 (s, 3 H); 3.87 (t, J=2.4 Hz, 1 H); 3.91 (m, 1 H); 4.26 (m, 1 H); 4.38 (dd, J=2.4 and 9.9 Hz, 1 H); 4.54 (d, J=8.0 Hz, 1 H); 4.67 (d, J=9.5 Hz, 1 H); 4.72 (m, 2 H); 5.04 (d, J=6.6 Hz. 1 H); 5.09 (dd, J=5.1 and 8.9 Hz, 1 H).
Step 2.2;
(2lb| mg of diastereoisomer 2.1.b of the preceding step are placed, under argon, in 2 ml of DCM and 65 pi of pyridine. The colourless solution is cooled to -10eC. 10 pi of trichloromethyl chloroformate are then added, stirring is continued at -10’C for 3 hours, and 5.7 mg (46.67 pmol) of 4-dimethy!aminopyridine are then added. The mixture is allowed to warm to room température, and stirring is then continued for 20 hours. The resulting mixture is concentrated under vacuum, the residue is taken up in 5 ml of EtOAc and the insoluble matter ls filtered off and rinsed with 2 ml of EtOAc. The filtrate is concentrated under vacuum. 55 mg of the compound obtained are dissolved in 2 ml of DMF. 53.4 mg of 4-(2-aminoethyl)pyridine are then added and the mixture is stirred for 48 hours at room température. The medium is poured onto an ice/water mixture. The resulting mixture is filtered by suction and the precipitate formed is then dried under vacuum. 34 mg ofthe expected product are obtained.
MS: method b
Rétention time Tr (min) = 1.16 ES+: [M+2HJ2+ m/z 611 (base peak); ES-: [MH+HCO2H]-: m/z 1265 (base peak)
1H NMR spectrum (500 MHz, in ppm, DMSO-de): 0.79 (d, J=6.9 Hz, 3 H); 0.89 to 1.11 (m, 30 H); 1.17 (m, 3 H); 1.64 to 2.18 (m, 12 H); 1.67 (s, 3 H); 2.07 (s, 3 H); 2.08 (s, 3 H); 2.27 (s, 3 H); 2.44 (d, J=13.2 Hz, 1 H); 2.55 (masked m, 1 H); 2.70 (m, 3 H); 2.85 (m, 1 H); 3.02 (m, 5 H); 3.35 (masked m, 1 H); 3.38 (s, 3H); 3.41 (s, 3 H); 3.67 (m, 3 H);
3.80 (m, 2 H); 3.78 (s, 3 H); 3.86 (s, 1 H); 4.14 (m, 1 H); 4.37 (dd, J=2.2 and 9.9 Hz, 1 H);
4.52 (d, J=8.0 Hz, 1 H); 4.57 (d, J=9.6 Hz, 1 H); 4.64 (d, J=9.3 Hz, 1 H); 4.75 (d, J=6.6 Hz, 1H); 4.96 (m, 1 H); 5.01 (d, J=6.6 Hz, 1 H); 6.89 (broad t, J=5.4 Hz, 1 H); 7.18 to 7.23 (m, 2 H); 8.43 (d, J=5.5 Hz, 2 H)
32.5 mg of the product prepared in the preceding step are piaced in 2 ml of MeOH with 11 mg of K2CO3. After stirring for 1 hour 30 minutes at room température, 20 ml of EtOAc are added to the reaction medium. The resulting mixture is washed with 20 ml of saturated aqueous NaCl solution. After séparation of the phases by settling, the organic phase is dried over MgSO<, fîltered and then evaporated to dryness under vacuum. 24 mg of the expected compound are obtained.
MS: method b
Rétention time Tr (min) = 0.97; [M+2HJ2+: 569 (base peak); [M-H+HCO2H]-: m/z
1181.
» ·
1H NMR spectrum (500 MHz, In ppm, DMSO-de): 0.78 (d, J=6.9 Hz, 3 H); 0.96 to 1.15 (m, 33 H); 1.64 to 1.87 (m, 6 H); 1.92 to 2.19 (m, 9 H); 2.25 (s, 3 H); 2.42 (d, J=13.4 Hz, 1 H); 2.55 (masked m, 1 H); 2.70 (m, 3 H); 2.85 (m, 2 H); 2.92 (dd, J=2.3and 8.1 Hz, 1 H); 3.01 (m, 2 H); 3.12 (m, 2 H); 3.30 (masked m, 1 H); 3.37 (s, 3 H); 3.45 (s, 3 H); 3.52 (m, 1 H); 3.61 (m, 2 H); 3.68 (broad s, 1 H); 3.80 (m, 4 H); 3.97 (m, 2 H); 4.28 (m, 1 H); 4.44 (d, J=8.0 Hz, 1 H); 4.53 to 4.65 (m, 2 H); 4.69 (d, J=4,7 Hz, 1 H); 4.86 (d, J=7.1 Hz, 1 H); 4.99 (m, 1 H); 5.38 (d, J=4.7 Hz, 1 H); 6.89 (m, 1 H); 7.23 (d, J=5.2 Hz, 2 H); 8.43 (d, J=5.5 Hz, 2 H).
EXAMPLE 3: Compound 3 (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(dimethylcarbamoy1)oxy]-2-(1{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-yl)-10-fl(2S,3R,6R)-3-hydfoxy-4-(methoxyimino)-6-methyltetrahydro-2Hpyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2Sl5R,7R)-2,4l5-trimethyl-1,4oxazepan-7-yl]oxy)oxacyclotetradecan-4-yl 3-methylbutanoate.
150 mg of compound 2.1.a obtained In step 2.1 of Example 2 are placed in 9 ml of DCM and 210 μΙ of pyridine in a 30 ml round-bottomed flask, under argon. The colourless solution Is cooled to -10eC. 30 μΙ of trichloromethyl chloroformate are then added and stirring is continued for 3 hours at -10’C, followed by addition of 17 mg of
4-dimethylaminopyridine dissolved In 2 ml of DCM. The mixture is allowed to warm to room température, and stirring is continued for 20 hours. The resulting mixture is concentrated under vacuum, the residue is taken up in 4 ml of DMF, and dimethylamine hydrochloride (173 mg) dissolved in DMF (2 ml) and TEA (0.3 ml) is then added. The reaction medium is stirred for 3 hours at room température. The resulting mixture is poured into an ice/water mixture, and the precipitate formed is filtered off by suction. 146 mg of product are recovered, which product is purified by chromatography on a Merck cartridge (5 g of 15-40 pm silica), eluting with a 95/5 DCM/MeOH mixture. 93 mg of the expected compound is obtained.
MS: method b
Rétention time Tr (min) » 1.33; [M+H]*; 1144
1H NMR spectrum (500 MHz, In ppm, DMSO-de): 0.79 (d, J=6.9 Hz, 3 H); 0.92 (m, 6 H); 0.96 (d, J=6.6Hz, 6 H); 1.05 (m, 18 H); 1.17 to 1.19 (m, 3 H); 1.69 to 2.03 (m, 9 H); 1.71 (s, 3 H); 2.05 (s, 3 H); 2.08 (s, 3H); 2.13 (m, 3 H); 2.21 (s, 3 H); 2.44 to 2.49 (masked m, 1 H); 2.72 (m, 6 H); 2.84 (broad s, 3 H); 3.03 (m, 3H); 3.33 (masked, 1 H); 3.39 (s, 3 H); 3.42 (s, 3 H); 3.65 (m, 3 H); 3.77 (s, 3 H); 3.80 (m, 1 H); 3.86 (t.J=2.6 Hz, 1 H); 3.89 (d, J=4.3 Hz, 1 H); 4.10 (m, 1 H); 4.37 (dd, J=2.5 and 9.9 Hz, 1 H); 4.52 (d, J=8.0 Hz, 1H); 4.59 (d, J=10.1 Hz, 1 H); 4.69 (d, J=9.6 Hz, 1 H); 4.73 (d, J=7.3 Hz, 1H); 4.83 (dd, J=3.8 and 7.9 Hz, 1H); 5.00 (d, J=7.3 Hz, 1 H).
Step 3.2:
mg of the product obtained in the preceding step are placed in 5.5 ml of MeOH, and 32.6 mg of K2CO3. After stirring for 1 hour 30 minutes at room température, 50 ml of
EtOAc are added to the reaction medium. The resulting mixture is washed with 20 ml of saturated aqueous NaCI solution. After séparation of the phases by settling, the organic phase is dried over MgSO4, filtered and then evaporated to dryness under vacuum. 50 mg of the expected compound is obtained.
MS: method b
Rétention time Tr (min) = 1.12; [M+H]*: 1060.
1H NMR spectrum (500 MHz, In ppm, DMSO-de): 0.78 (d, J=6.9 Hz, 3 H); 0.92 (m, 6 H); 0.96 (d, J=6.6 Hz, 6 H); 1.01 to 1.14 (m, 21 H); 1.70 to 2.06 (m, 9 H);
1.71 (s, 3 H); 2.09 to 2.17 (m, 3 H); 2.19 (s, 3 H); 2.38 (dd, J=9.4 and 14.0 Hz, 1 H); 2.59 (m, 1 H); 2.79 (m, 9 H); 2.92 (dd, J=2.6 and 8.0 Hz, 1 H); 3.02 (m, 2 H);
3.30 (masked m, 1 H); 3.38 (s, 3 H); 3.46 (s, 3 H); 3.51 (m, 1 H); 3.63 (dd, J=4.4 and
9.6 Hz, 1 H); 3.67 (broad s, 1 H); 3.71 (d, J=6.9 Hz, 1 H); 3.77 (d, J=5.4 Hz, 1 H); 3.83 (m, 4 H); 3.89 (t, J=4.9 Hz, 1 H); 4.21 (m, 1 H); 4.45 (d, J=7.9 Hz, 1 H); 4.62 (m, 3 H); 4.88 (m, 2 H); 5.24 (d, J=4.6 Hz, 1 H).
EXAMPLE 4: Compound 4 (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-2-(1-{[(2Rl3R,4R,5R,6R)-5-hydroxy-3(4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy)propan-2-yl)-10-{[(2S13R,6R)-3-hydroxy-
4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-7-{[(2methy!-1-[[(5-nitro-1H-pyrazol-4-yl)sulfonyl]amino}propan-2-yl)carbamoyl]oxy}-6,14-dioxo12-{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy)oxacyclotetradecan-4-yl 3methylbutanoate.
102 mg of the product obtained in Préparation 3 are placed in 2 ml of MeOH. The solution is cooled to 0°C, and a solution of 86 mg of sodium metaperiodate in water (2 ml) is added. The reaction mixture is stirred magnetically at room température for 5 hours. 15 ml of DCM are added and the mixture is washed with 10 ml of water and then with 10 ml of saturated aqueous NaCI solution. The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. 86 mg of product obtained are dissolved in MeOH (10 ml), the solution is cooled to 0°C and methylamine (84 pl of a 2M solution in THF) and then acetic acid (9.7 μΙ) are added. After stirring for 10 minutes at 0’C, 13.34 mg of NaBHsCN are added. The reaction medium is stirred for 1 hour at 0°C and is then allowed to warm to room température, and stirring is continued for 20 hours. 20 ml of DCM are added and the mixture is washed with 15 ml of saturated aqueous NaHCOs solution and then with 15 ml of saturated aqueous NaCI solution. The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. 0.12 g of product obtained is purified by préparative LC/MS, eluting with a 15/85 to 95/5 gradient of acetonitrile/water containing 0.1% TFA. The fractions of mass 1278 to 1281 are recovered. The recovered phases are brought to pH 8 with saturated aqueous NaHCOs solution and then extracted with 50 ml of EtOAc. The organic phase is dried over MgSO4, filtered and then evaporated to dryness under vacuum. 38 mg of the expected product are obtained.
MS: method b
Rétention time Tr (min) = 1.06; [M+Na]+: 1278
1H NMR spectrum (500 MHz, in ppm, DMSO-dt): 70/30 mixture of the diastereoisomers, 0.78 (d, J=6.8 Hz, 3 H); 0.91 (d, J=6.8 Hz, 3 H); 0.95 (m, 9 H); 1.02 to 1.16 (m, 27 H); 1.68 (broad s, 3 H); 1.71 to 1.90 (m, 4 H); 1.93 to 2.21 (m, 8 H); 2.36 (broad s, 2.1 H); 2.46 (broad s, 0.9 H); 2.61 (m, 1 H); 2.69 to 3.06 (m, 9 H); 3.30 (masked m, 1 H); 3.38 (s, 3 H); 3.46 (s, 3 H); 3.49 to 3.64 (m, 2.3 H); 3.67 (t, J=2.6 Hz, 1 H); 3.72 (m, 1 H); 3.78 to 3.91 (m, 2.7 H); 3.80 (s, 3 H); 4.30 (m, 1 H); 4.45 (d, J=7.9 Hz, 1 H); 4.57 to 4.67 (m, 3 H); 4.83 (d, J=6.8 Hz, 1 H); 4.96 (dd, J=3.0 and 9.2 Hz, 0.7 H); 5.04 (dd, J=4.8 and 8.6 Hz, 0.3 H); 5.26 (broad s, 0.7 H); 5.36 (broad s, 0.3 H); 6.32 (broad s, 1 H); 6.70 m, 1 H); 7.89 to 7.93 (m, 1 H).
EXAMPLE 5: Compound 5
Compound 5-a: (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-2-(1{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy)propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2Hpyran-2-yl]oxy)-3,5,7,9,11,13-hexamethyl-7-([(2-methyl-1-([(2nitrophenyl)sulfonyl]amino}|aOpan-2-yl)carbamoyl]oxy}-6,14-dioxo-12-fl(2S,5R17R)-2,4,5trimethyl-1,4-oxazepan-7-yl]oxy)oxacyclotetradecan-4-yl 3-methylbutanoate.
Compound 5-b: (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-2-(1{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2• · yl]oxy}propan-2-yl)-10-{[(2S,3Rl6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2Hpyran-2-yl]oxyJ-3,5,7,9,11,13-hexamethyl-7-{[(2-methyl-1-{[(2nitrophenyl)sulfonyl]amino)propan-2-yl)carbamoyl]oxy}-6114-dioxo-12-{[(2S,5S,7R)-214l5trimethyl-1,4-oxazepan-7-yl]oxy)oxacyclotetradecan-4-yl 3-methylbutanoate.
(5 b)
A solution of 99 mg of the product obtained in Préparation 4 in 2 ml of MeOH is cooled to 0°C. A solution of 83 mg of NaIOx in 2 ml of water is then added dropwise. After 15 minutes at O’C, the mixture is allowed to warm to room température, and stirring is continued for 3 hours. The réaction medium is poured into 20 ml of DCM. The resulting mixture is washed with 10 ml of water, the phases are separated by settling and then washed again with 10 ml of saturated aqueous NaCI solution. The organic phase is dried over MgSOx, filtered and then evaporated to dryness. 110 μΙ of a 2M solution of methylamine in THF, 13.9 μΙ of AcOH and finally 16.67 mg of NaBHsCN are added, in this order, to a solution of 95 mg of the compound thus obtained in 8 ml of MeOH. The mixture is stirred for 20 hours at room température. 20 ml of DCM are added and the resulting mixture is washed with saturated aqueous NaHCOj solution and then with aqueous NaCI solution. The aqueous phases are extracted with DCM. The organic phases are combined, dried over MgSO4, filtered and then evaporated to dryness. The 85 mg of product obtained are combined with another batch of 68 mg prepared in a preceding reaction under the conditions described above. This mixture is purified by chromatography on silica (10 g of 15-40 pm silica) with a 94.5/5.5 DCM/MeOH elution solvent. 49 mg of diastereoisomer 5-a and 30 mg of isomer 5-b are obtained.
Compound 5-a:
MS: method b
Rétention time Tr (min) = 1.16; [M+H]*: 1288
1H NMR spectrum (500 MHz, In ppm, DMSO-dt): 0.78 (d, J=6.8 Hz, 3 H); 0.90 (d, J=6.8 Hz, 3 H); 0.92 to 0.97 (m, 9 H); 1.00 to 1.17 (m, 27 H); 1.62 to 1.70 (m, 4 H); 1.71 to 1.85 (m, 4 H); 1.89 to 2.08 (m, 4 H); 2.13 (s, 3 H); 2.19 (s, 3 H); 2.39 (dd, J=9.7 and 14.2 Hz, 1 H); 2.59 (m, 1 H); 2.74 (m, 2 H); 2.83 to 3.11 (m, 6 H); 3.28 (masked m, 1 H); 3.38 (s, 3 H); 3.46 (s, 3 H); 3.52 (quint, J=6.2 Hz, 1 H); 3.62 (dd, J=4.4 and 9.8 Hz, 1 H); 3.68 (m, 2 H); 3.76 (d, J=4.5 Hz, 1 H); 3.82 (m, 5 H); 4.26 (quint, J=7.2 Hz, 1 H); 4.45 (d. J=7.9 Hz, 1 H); 4.59 (d, J=9.9 Hz, 1 H); 4.68 (m. 2 H); 4.83 (d, J=7.1 Hz, 1 H); 4.91 (dd, J=2.8 and 9.2 Hz, 1 H); 5.23 (d, J=4.4 Hz, 1 H); 6.28 (s, 1 H); 7.91 (m, 5 H).
Compound 5-b:
MS: method b
Rétention time Tr (min) = 1.16; [M+H}*: 1288
1H NMR spectrum (500 MHz, In ppm, DMSO-de): 0.78 (d, J=6.8 Hz, 3 H);
I0 0.90 (d, J=7.0 Hz, 3 H); 0.95 (d, J=6.7 Hz, 9 H); 1.00 (d. J=6.7 Hz, 3 H); 1.05 (m, 9 H); 1.09 (d, J=6.2 Hz, 3 H); 1.13 (m, 9 H); 1.24 (s, 3 H); 1.66 (s, 3 H); 1.78 (m, 4 H); 1.99 (m, 4 H); 2.13 (m, 4 H); 2.25 (s. 3 H); 2.42 (d, J=13.0 Hz, 1 H); 2.53 (m, 1 H); 2.74 (quint, J=7.3 Hz, 1 H); 2.87 (m, 4 H); 2.98 (q, J=6.4 Hz, 1 H); 3.07 (m, 2 H); 3.32 (masked m, 1 H); 3.37 (s, 3 H); 3.46 (s, 3 H); 3.52 (m. 1 H); 3.62 (m, 2 H); 3.67 (t, J=2.5 Hz, 1 H);
3.80 (m, 4 H); 3.88 (m, 2 H); 4.29 (quint, J=7.8 Hz, 1 H); 4.44 (d, J=7.9 Hz, 1 H); 4.58 (d,
J=9.3 Hz, 1 H); 4.63 (d, J=9.4 Hz, 1 H); 4.72 (d, J=4.5 Hz, 1 H); 4.83 (d. J=7.2 Hz, 1 H); 5.00 (dd, J=4.5 and 9.1 Hz, 1 H); 5.35 (d, J=4.5 Hz, 1 H); 6.27 (broad s, 1 H); 7.74 to 8.05 (m, 5 H).
EXAMPLE 6: Compound 6 (2R,3S,4R,5R.7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,7R)-4(2-fluoroethyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-
3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S13Rl6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl}oxy}-3,5,7,9,11,13- hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate.
0.5 g of the compound obtained In Préparation 2 Is placed In 10 ml of MeOH.
The solution obtained is cooled to 0eC. A solution of 0.475 mg of sodium metaperiodate in 10 ml of water is then rapidly added dropwise. After 15 minutes at 0°C, the mixture is allowed to warm to room température, and stirring is continued for 5 hours. The medium is saturated with NaCI (-3 g) and taken up in DCM (40 mi). The precipitate is fiitered off and washed with saturated aqueous NaCI solution. The aqueous phase is extracted with DCM. The organic phases are combined, dried over MgSO< filtered and then evaporated to dryness under vacuum. 443 mg of the expected product are obtained.
100 mg of this compound are dissolved in 2.2 ml of MeOH, followed by addition, in the following order, of 25 pl of TEA, 22 mg of 2-fluoroethylamine hydrochloride, 12.7 μΙ of acetic acid and finally 16.8 mg of NaBHsCN. The medium is stirred for 20 hours at room température. 20 ml of DCM are added and the resulting mixture is washed with saturated aqueous sodium bicarbonate solution and then with aqueous NaCI solution. The aqueous phases are extracted with DCM. The organic phases are combined, dried over Na2SO4. filtered and then evaporated to dryness. 92 g of the product obtained are purified by chromatography on silica (5 g of 15-40 pm silica) with a 97/3 DCM/MeOH eluent mixture. The expected product is obtained in the form of a mixture of diastereoisomers.
MS: method b
Rétention time Tr (min) = 1.28; [M-H+HCO2H]-: m/z 1198.
1H NMR spectrum (500 MHz, in ppm, DMSO-de): 70/30 mixture of the diastereoisomers 0.78 (d, J=6.8 Hz, 3 H); 0.91 (d, J=6.9 Hz, 3 H); 0.94 (d, J=7.3 Hz, 3 H); 0.98 (dd, J=1.6 and 6.6 Hz, 6 H); 1.01 to 1.16 (m, 21 H); 1.60 to 2.22 (m, 15 H);
2.52 (masked m, 1 H); 2.59 (d, J=5.0 Hz, 1 H); 2.68 to 3.08 (m, 9 H); 3.28 (masked m, 1 H); 3.38 (s, 3 H); 3.46 (s, 3 H); 3.52 (m, 1 H); 3.64 (m, 2 H); 3.72 to 3.93 (m, 7 H);
4.10 (d, J=6.0 Hz, 2 H); 4.24 (m, 1 H); 4.41 (m, 3 H); 4.56 to 4.72 (m, 3 H); 4.83 (d, J=7.1 Hz, 1 H); 4.88 (m, 0.7 H); 4.99 (dd, J=4.0 and 9.1 Hz, 0.3 H); 5.13 (d, J=4.6 Hz, 0.7 H); 5.31 (d, J=4.6 Hz, 0.3 H); 7.28 (m, 5 H).
EXAMPLE 7: Compound 7
Compound 7-a: (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7[(benzylcarbamoyl)oxy]-2-(1-{I(2R,3Rl4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate.
e ·
Compound 7-b: (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7[(benzylcarbamoyl)oxy]-2-(1-{[(2Rl3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6methyltetrahydro-2H-pyran-2-ylIoxy)propan-2-yl)-10-([(2S,3R,6R)-3-hydroxy-4(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy )-3,5,7,9,11,13-hexamethyl-6,14dioxo-12-{{(2S,5S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate.
(7-a) (7.b)
0.68 g of the compound obtained in Préparation 2 is placed in THF (7 ml). The solution obtained ls cooled to 0’C. A solution of sodium metaperiodate in 7ml of water ls then rapidly added. After 15 minutes at 0’C, the mixture is allowed to warm to room température, and stirring is continued for 6 hours. The precipitate formed is filtered off and rinsed with 7 ml of THF. A 2N solution of methylamine in 1.21 ml of THF and then 139.04 pl of acetic acid are added. After stirring for 5 minutes at room température, 199.63 mg of NaBHjCN are added. The suspension obtained is stirred at room température for 20 hours. The precipitate formed is filtered off and rinsed with 50 ml of DCM. The filtrate is washed with 30 mi of saturated aqueous NaHCOj solution and then with 30 ml of saturated aqueous NaCI solution. The aqueous phases are extracted with 50 ml of DCM. The organic phases are combined, dried over MgSO«, filtered and then evaporated to dryness under vacuum. The product obtained is purified by chromatography on a Merck cartridge (50 g of 15-40 pm silica), eluting with a 94/6 CHCh/MeOH mixture. 320 mg of the expected compound 7-a, 77 mg of the other diastereoisomer 7-b and 147 mg of a mixture of diastereoisomers are obtained.
Compound 7-a:
MS: method b
Rétention timeTr (min) ~ 1.31; [M-H+HCO2H]·: m/z 1166 (base peak).
1H NMR spectrum (500 MHz, In ppm, DMSO-de + CDjCOOD): 0.81 (d, J=6.9 Hz, 3 H); 0.93 (d, J=6.8 Hz, 3 H); 0.95 to 1.02 (m, 9 H); 1.05 to 1.17 (m, 15 H); 1.24 (d, J=6.0 Hz, 3 H); 1.30 (d, J=6.6 Hz, 3 H); 1.74 (m, 7 H); 2.04 (m, 3 H); 2.18 (m, 5 H); 2.78 (s, 3 H); 2.79 (m, 1 H); 2.89 (d, J=14.8 Hz. 1 H); 2.93 (dd, J=2.5 and 8.0 Hz, 1 H); 3.03 (m, 2 H); 3.13 (m, 1 H); 3.35 (m, 2 H); 3.40 (s, 3 H); 3.45 (m, 1 H); 3.48 (s, 3 H); 3.51 (m, 2 H); 3.68 (m, 2 H); 3.82 (s, 3 H); 3.87 (m, 2 H); 3.94 (d, J=4.9 Hz, 1 H);
4.13 (d, J=5.7 Hz, 2 H); 4.45 (m, 2 H); 4.62 (m, 3 H); 5.12 (dd, J=4.5 and 8.4 Hz, 1 H); 7.28 (m, 6 H).
Compound 7-b:
MS: method b
Rétention time Tr (min) - 1,32; [M-H+HCOîH]': m/z 1166 (base peak).
1H NMR spectrum (500 MHz, In ppm, DMSO-de + CDjCOOD): 0.82 (d, J=6.9 Hz, 3 H); 0.94 (d, J=6.8 Hz, 3 H); 1.02 (m, 9 H); 1.08 (m, 6 H); 1.14 (m, 9 H); 1.22 (d, J=6.1 Hz, 3 H); 1.34 (d, J=6.8 Hz, 3 H); 1.75 (s. 3 H); 1.82 (m, 3 H); 1.90 to 1.95 (masked m, 1 H); 1.99 (m, 2 H); 2.09 (m, 1 H); 2.19 (m, 3 H); 2.35 (m, 2 H);
2.69 (m, 1 H); 2.79 (s, 3 H); 2.96 (m, 2 H); 3.04 (m, 2 H); 3.15 (dd, J=9.6 and 13.6 Hz, 1 H); 3.23 (d, J=13.6 Hz, 1 H); 3.32 (dd, J=4.8 and 9.7 Hz, 1 H); 3.40 (s, 3 H); 3.48 (s, 3 H); 3.53 (m, 2 H); 3.66 (m, 2 H); 3.70 (t, J=1.0 Hz, 1 H); 3.80 (m, 4 H); 3.94 (d, J=5.2 Hz, 1 H); 4.06 (broad s, 1 H); 4.14 (m, 2 H); 4.38 (m, 1 H); 4.47 (d, J=7.9 Hz, 1 H); 4.56 (m, 3 H); 5.15 (m, 1 H); 7.21 to 7.33 (m, 6 H).
Alternative for the préparation of compound 7-a
<7.a)
0.2 ml of CHCh, 12 mg of compound 8-a of Example 8,108 pl of 0.1 M formic acid and 3 pl of formaldéhyde are added together with stirring, under argon, and the mixture is heated for 30 minutes at 50’C. The reaction medium is neutralized with saturated « · aqueous sodium bicarbonate solution and extracted with DCM. The organic phase is dried over MgSÛ4, filtered and then evaporated to dryness under vacuum. The residue obtained is purified by chromatography on silica (2.5 g of 15-40 pm SiOH) with a 95/5 to 90/10 CHCIa/MeOH elution gradient. 6.2 mg of the expected product are obtained.
Other alternative for the préparation of compound 7-a
G a)
Step 1
1.35 g of compound 1-a of Example 1 and 1.11 g of N.N'-carbonyldiimidazole are placed in 8 ml of cyclohexane. The mixture is heated at 100’C for 35 minutes by microwave. The heterogeneous medium is taken up in 60 ml of DCM and washed with 40 ml of water and then with 40 ml of saturated NaCI solution. The aqueous phases are re-extracted with 60 ml of DCM. The organic phases are combined, dried over MgSO*, filtered and then evaporated to dryness under vacuum. 1.7 g of the expected compound Is obtained.
MS: method e
Rétention time Tr (min) = 3.67; [M+H]*: 1271 « «
1.7 g of the compound prepared in step 1 are placed in 17 ml of THF. 6.84 ml of 1 M HCl are added. The mixture Is stirred for 3 hours at room température. 50 ml of DCM are added and the resulting mixture is washed with saturated NaHCOs solution (20 ml) and then with saturated NaCI solution (20 ml). The aqueous phases are re-extracted with 50 ml of DCM. The organic phases are combined, dried over MgSO<, filtered and then evaporated to dryness under vacuum. 1.48 g of the expected product are recovered.
MS: method e
Rétention time Tr (min) = 3.41; [M+H]*: 1083
σ-a) g of the product prepared above is placed In DMF (10 ml). Benzylamine (305.54 μΙ) and 1,8-diazabicyclo[5.4.0]undec-7-ene (168.87 μΙ) are added. The mixture Is stirred at room température for 24 hours. The resulting mixture is extracted with 60 ml of EtOAc and washed with 30 ml of water and then with 30 ml of saturated NaCI solution. The aqueous phases are re-extracted with 60 ml of EtOAc. The organic phases are combined, dried over MgSO<, filtered and then evaporated to dryness under vacuum.
1.1 g of a yellow oil are obtained. The product Is purified by chromatography on a Merck so cartridge (50 g of 15-40 pm SiOH), eluting with a 98/2 EtOAc/TEA mixture. 400 mg of the expected compound is obtained.
EXAMPLE 8: Compound 8
Compound 8-a: (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7[(benzylcarbamoyl)oxy]-12-{[(2Sl5R,7R)-2,5-dimethyHI4-oxazepan-7-yl]oxy}-2-(1{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-yl)-10-{[(2Sl3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2Hpyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 310 methylbutanoate.
Compound 8-b: (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7[(benzylcarbamoyl)oxy]-12-{[(2S,5S,7R)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1{[(2R,3R,4R,5R16R)-5-hydroxy-3I4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H15 pyran^-ylJoxyî-S.SJ.g.l 1,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3methylbutanoate.
• » ml of toluene, 0.2 g of the product obtained in Préparation 1 and 196 mg of N,N'carbonyldiimidazole are placed under argon. The reaction medium is heated for 3 hours at 80C and then concentrated under vacuum. DCM is added and the resulting mixture is then washed with saturated aqueous NaCI solution. The organic phase is dried over MgSO<, filtered and then evaporated to dryness under vacuum. The residue is purified by chromatography (10 g of 15-40 pm silica) with a 98/2 to 95/5 DCM/MeOH elution gradient. 112 mg of the expected compound is obtained.
MS: method b
Rétention time Tr (min) = 1.63; [M+H]*: 1300
Step 8.2:
HO-VJ —d* 'b— ml of THF, 240 mg of the macrolide prepared in step 8.1 and 369 pl of 1 M HCl are stirred together under argon. The pale yellow homogeneous medium is stirred overnight at room température. A further 369 pl of 1 M HCl are added and stirring is continued for 24 hours. The reaction medium is neutralized with saturated aqueous sodium bicarbonate solution. The resulting mixture is extracted with EtOAc. The organic phase is dried over MgSO^ filtered and then evaporated to dryness under vacuum. 181 mg of the residue obtained are purified by chromatography (10 g of 15-40 pm silica) with a 50/50 to 70/30 EtOAc/heptane elution gradient. 87 mg of the expected compound is obtained.
MS: method b
Rétention time Tr (min) = 1.56; [M-H+HCO2H]*: m/z 1156 (base peak).
Step 8.3:
ml of DMF, 1 g of the compound obtained in step 8.2,188 μΙ of 1,8-diazabicyclo [5.4.0]undec-7-ene and 138 μΙ of benzylamine are stirred together under argon. The homogeneous medium is stirred ovemight at room température. 20 g of Ice are added to the réaction medium and the resulting mixture is then extracted with 3 « 20 ml of EtOAc. The organic phases are combined and washed with 20 ml of saturated aqueous NaCI solution, and the organic phase Is dried over MgSOe, filtered and then evaporated to dryness under vacuum. 975 mg of residue are purified by chromatography (50 g of 1540 pm silica), eluting with a 7/3 EtOAc/heptane mixture. 490 mg of the expected compound is obtained.
MS: method b
Rétention time Tr (min) = 1.68; [M-H+HCO2HF: m/z 1195 (base peak).
1H NMR spectrum (500 MHz, in ppm, DMSO-de): 0.79 (d, J=6.9 Hz, 3 H); 0.88 to 1.01 (m, 12 H); 1.05 (m, 6 H); 1.11 (m, 6 H); 1.14 (d, J=6.0 Hz, 3 H); 1.30 (d, J=5.5 Hz, 3 H); 1.52 (s, 3 H); 1.67 to 1.86 (m, 4 H); 1.71 (s, 3 H); 1.94 to 2.10 (m, 4 H); 2.15 (m, 4 H); 2.36 (dd, J=5.1 and 13.6 Hz, 1 H); 2.77 (m, 2 H); 2.92 (dd, J=2.5 and 8.0 Hz, 1 H); 3.01 (m, 2 H); 3.27 to 3.32 (masked m, 1 H); 3.37 (s, 3 H); 3.45 (s, 3 H);
3.52 (m, 2 H); 3.61 to 3.68 (m, 2 H); 3.80 (s, 3 H); 3.84 (d, J=6.9 Hz, 1 H); 3.95 (m, 2 H);
4.13 (m, 3 H); 4.45 (d, J=8.0 Hz, 1 H); 4.55 (d, J=9.9 Hz, 1 H): 4.65 (m, 2 H); 4.87 (d, J=7.1 Hz, 1 H); 4.99 (dd, J=5.4 and 8.4 Hz, 1H); 5.43 (m, 1 H); 7.26 (m, 5 H); 7.38 (broad t, J=6.0 Hz, 1 H).
Step 8.4:
ml of MeOH, 300 mg of the macrolide prepared in the preceding step and
108 mg of K2CO3 are stirred together under argon. The reaction medium is stirred for 5 24 hours at room température, followed by addition of a further 72 mg of K2CO3. The reaction medium is stirred for a further 24 hours, and 30 ml of saturated aqueous NaCI solution are then added. The resulting mixture is extracted with EtOAc (3 x 100 ml). The organic phase is separated out after settling of the phases, dried over MgSCL, filtered and then evaporated to dryness. 300 mg of the residue obtained are purified by 10 chromatography (30 g of 15-40 pm silica), eluting with a 7/3 EtOAc/heptane mixture. 265 mg of the expected product are obtained.
Step 8.5:
(8.a)
3.5 ml of THF and 340 mg of the compound obtained in the preceding step are stirred together under argon. The solution obtained is cooled to O’C, followed by dropwise addition of an aqueous solution of 325 mg of sodium metaperiodate in 3.5 ml of water. Stirring is continued at O’C for 10 minutes, and the mixture is then allowed to warm to room température. After stirring for 5 hours 30 minutes, the precipitate formed is filtered off and rinsed with 4 ml of THF. 64.8 mg of NH«CI are added to the filtrate obtained, followed, after stirring for 5 minutes at room température, by 95 mg of NaBHjCN. The reaction medium is stirred at room température for 20 hours. The precipitate formed is filtered off and rinsed with DCM. The filtrate is washed with saturated sodium bicarbonate solution and then with aqueous NaCI solution. The aqueous phases are extracted with DCM. The organic phases are combined, dried over MgSO«, filtered and then evaporated to dryness under vacuum. The 278 mg of residue are purified by chromatography on silica (20 g of 15-40 μ SiOH) with a 98/2 to 95/5 CHCIj/MeOH elution gradient. 120 mg of diastereoisomer 8-a and 14 mg of diastereoisomer 8-b are obtained.
Compound 8-a:
MS: method b
Rétention time Tr (min) - 1.3; [M-H+HCO2H]·: m/z 1152 (base peak).
1H NMR spectrum (500 MHz, In ppm, DMSO-de): 0.78 (d, J=6.6 Hz, 3 H);
0.91 (d, J=6.9 Hz, 3 H); 0.95 (d, J=7.1 Hz, 3 H); 0.99 (d, J=6.6 Hz, 6 H); 1.03 to 1.12 (m, 21 H); 1.75 (m, 8 H); 1.99 (m, 4 H); 2.15 (m, 3 H); 2.50 (masked m, 1 H); 2.68 to 2.94 (m, 5 H); 3.01 (m, 2 H); 3.29 (masked m, 1 H); 3.38 (s, 3 H); 3.45 (s, 3 H); 3.52 (m, 1 H); 3.61 to 3.90 (m, 6 H); 3.80 (s, 3 H); 4.10 (m, 3 H); 4.45 (d, J=7.7 Hz, 1 H); 4.62 (m, 3 H); 4.86 (d, J=7.1 Hz, 1 H); 4.95 (m, 1 H); 5.26 (d, J=4.4 Hz, 2 H); 7.20 to 7.32 (m, 5 H); 7.36 (t, J=6.0 Hz, 1 H).
Compound 8-b:
MS: method b
Rétention time Tr (min) = 1.12; [M-H+HCO2H]·: m/z 1152 (base peak).
1H NMR spectrum (500 MHz, in ppm, DMSO-de): 0.78 (d, J=6.9 Hz, 3 H); 0.91 (d, J=6.6 Hz, 3 H); 0.98 (m, 9 H); 1.03 to 1.16 (m, 21 H); 1.69 to 2.20 (m, 12 H);
1.72 (s, 3 H); 2.71 (m, 3 H); 2.92 (m, 2 H); 3.01 (m, 3 H); 3.10 (m, 1 H); 3.34 (masked m, 1 H); 3.38 (s, 3 H); 3.45 (s, 3 H); 3.52 (m, 1 H); 3.63 (dd, J=4.5 and 9.7 Hz, 1 H); 3.67 (broad s, 1 H); 3.71 to 3.81 (m, 3 H); 3.79 (s, 3 H); 3.87 (t, J=4.7 Hz, 1 H); 4.09 (m, 3 H); 4.45 (d, J=8.0 Hz, 1 H); 4.60 (m, 3 H); 4.83 (d, J=6.9 Hz, 1 H); 5.01 (m, 1 H); 5.14 (d, J=3.6 Hz, 1 H); 7.20 to 7.35 (m, 6 H).
Table 1: Structures and analyses of compounds prepared according to one of the processes described in Examples 1 to 8 above and 9 to 11 below.
| Compound | CHEM1STRY | LCSM | ||
| Méth | Tr | MS | ||
| 9 | Mil0 «r-Uy / œ | a | 1,02 | [M-H+HCO2H]-: m/z 1196 (basepeak) |
| 10 | 4¾ «r-xJy / œ | a | 1,01 | [M-H+HCO2H]- : m/z 1196 (basepeak) |
| 11 | Web O <S.il | a | 1,04 | [M-H+HCO2HJ- : m/z 1224 (basepeak) |
| 12 | cp | a | 1,03 | [M-H+HCO2H]- : m/z 1224 (basepeak) |
| 13 | Wftv~o | b | 1,04 | [M-H+HCO2HJ-: m/z 1180 (basepeak) |
| Compound | CHEMISTRY | LCSM | ||
| Méth | Tr | MS | ||
| 14 | •ni J fi OH | b | 1,19 | [M+HJ+ : 1225 |
| 15 | b | 1*2 1,25 | [M+HJ+ : 1253, mixture of isomers | |
| 16 | w^. A | b | 1,2 | [M+HJ+: 1251 |
| 17 | b | 131 | [M-H+HC02H]- : m/z 1237 (base peak) | |
| 18 | Wt^O | b | 1,32 | [M+H]+ : 1221 |
| Compound | CHEMISTRY | LCSM | ||
| Méth | Tr | MS | ||
| I9 | b | 136 | [M-H+HCO2H]- : m/z 1240 (base peak) | |
| 20 | W | b | 1,16 | [M+HJ+ : 1296 |
| 21 | 0J | b | 1,17- 1,19 | m/z 306 (base peak) mixture of isomers |
| 22 | £- | b | 136 | [M+H]+ : 1273 |
| 23 | -£§1 0A o | b | 1,29 | m/z 1251 (base peak) mixture of isomers |
| Compound | CHEMISTRY | LCSM | ||
| Méth | Tr | MS | ||
| 24 | fa | b | 1,2 | m/z : 207 (base peak) ; [MH+HCO2H]-: m/z 1257 |
| 25 | fa | b | 1,53 | [M-H+HCO2H]- : m/z 1272 (base peak) |
| 26 | -fa | b | 1,04 | [M+2HJ2+: 619 (base peak) ; [M-H+HCO2H]-: m/z 1280 |
| 27 | Wa -< 1 i* “ r ? | b | 1,21 | [M-H+HCO2H]- : m/z 1164 (base peak) |
| 28 | fa | b | M | [M+H]+: 1225 |
| Compound | CHEMISTRY | LCSM | ||
| Méth | Tr | MS | ||
| 29 | b | U - 1,21 | [M+HJ+ : 1223 mixture of isomers | |
| 30 | b | 1,09 | [M+H]+: 1197 | |
| 31 | b | 1,11 | [M+HJ+: 1211 | |
| 32 | çor | b | 1,17 | [M-H+HC02HJ- : m/z 1240 |
| 33 | o | b | 1,18 | [M+HJ+: 1273 |
| Compound | CHEMISTRY | LCSM | ||
| Méth | Tr | MS | ||
| 34 | OV / ” | b | 1,1 | [M+H]+: 1267 |
| 35 | -o o— r°N #—C / 1 p OH | b | 135 | [M-H+HC02H]- : m/z 1192 |
| 36 | yjrr ' | b | 1,16- 1,17 | [M+H1+: 1311 mixture of isomers |
| 37 | —«\J J* “* | b | 138 | [M-H+HC02H]-: m/z 1268 (bascpeak) |
| 38 | F ^C/ ** | b | 135 | [M-H+HC02H]-: m/z 1254 (base peak) |
| Compound | CHEMISTRY | LCSM | |||
| Méth | Tr | MS | |||
| 39 | CH | b | 1,3 | [M-H+HCO2HJ-: m/z 1272 (base peak) | |
| 40 | Web0 011 | b | 1,33 (d) | m/z : 265 (base peak) ; [M-H+HCO2HJ-: m/z 1315mixture of isomers | |
| 41 | b | 1,29 (d) | m/z : 250 (base peak) ; [M-H+HCO2H]- : m/z 1300 mixture of isomers | ||
| 42 | -ify -/v 0 | H ? | b | 1,25 | m/z : 263 (base peak) ; [M-H+HCO2HJ- : m/z 1313 |
| 43 | -îT§ -« >- >o | Ho g CH Λ | b | 1,24 | [M-H+HCO2H]- : m/z 1169 (base peak) |
| Compound | CHEMISTRY | LCSM | |||
| Méth | Tr | MS | |||
| 44 | -o a- 0 | Ho 1 /4 CH Z | b | 1,30- 1,32 | [M+HJ+ : 1226 mixture of isomers |
| 45 | n | b | 1,23 | m/z : 267 (base peak) ; [M-H+HCO2HJ-: m/z 1317 | |
| 46 | ο k P Ύ \ 1 fr'^'r >*>{/ * - - | Ho 'd. Z | b | 1,29 | [M-H+HCO2H]- : m/z 1295 (base peak) |
| 47 | o *s^* \ **·< yj «ôr Ί MO<J 1 o- V\ Y J-i c-A | Ho 1 CK /· | b | 133 | m/z : 330 (base peak) |
| 48 | Wt w * °- ŸAr^ | Ho il N OH /* | b | 0,99 | m/z : 258 (base peak) ; [MH+HCO2H]- : m/z 1308 |
| Compound | CHEMISTRY | LCSM | |||
| Méth | Tr | MS | |||
| ο | |||||
| 49 | —0.0— fj- | 1 ' P | b | 1,28 | [M-H+HC02H]- : m/z 1365 |
| w | çW | ||||
| 50 | y | b | 1.15 (d) | [M-H+HCO2HJ- : m/z 1351 mixture of isomers | |
| J / ” | |||||
| ο k | |||||
| 51 | —O Q— | r /* P | b | 1,25- 1,29 | m/z : 327 (base peak) ; m/z : 301 (base peak) |
| }-“~O | |||||
| 52 | HO-fjl 1 -° | Î /.OH P | b | 1.14 | m/z : 315 (base peak) |
| Wr | pO | ||||
| 53 | -jTY | J — _—A J d | b | 1.12 | m/z : 315 (base peak) |
| 1 /~ |
| Compound | CHEMISTRY | LCSM | ||
| Méth | Tr | MS | ||
| 54 | O? | d | 2,20- 222 | [M-H+HCO2H]- : m/z 1286 (base peak) mixture of isomers |
| 55 | b | I,06 | [M+2HJ2+: 637 (base peak) | |
| 56 | » y/O /¾ | d | 2,36- 239 | [M-H+HCO2H]- : m/z 1222 (base peak) mixture of isomers |
| 57 | h | b | 238- 2,41 | m/z : 345 (base peak) mixture of isomers |
| 58 | >, μΌ -OO- | b | 1,21- 1,23 | m/z 306 (base peak) ; [M-H+HCO2H]- : m/z 1330 mixture of isomers |
| Compound | CHEMISTRY | LCSM | ||
| Méth | Tr | MS | ||
| 59 | ο y | b | 1,16 | [M-H+HCO2H]- : m/z 1301 (base peak) |
| 60 | b | 1,18 | [M-H+HCO2H]- : m/z 1194 (base peak) | |
| 61 | J | b | 1 | [M+2HJ2+: 630 (base peak) |
| 62 | b | 1,12 | [M+H]+: 1301 | |
| 63 | -¾ | b | 1,08 | m/z : 1035 (base peak) |
| Compound | CHEMISTRY | LCSM | ||
| Méth | Tr | MS | ||
| 64 | φ- | b | 133- 134 | [M+2H]2+: 666 - m/z :248 (base peak) mixture of isomers |
| 65 | -ο λ- * i y* | b | 1,13 | [M+HJ+: 1315 |
| 66 | b | 1,16 | [M-H+HCO2H]- : m/z 1033 (base peak) | |
| -o o- A’cJ $—ί * 04 | ||||
| 67 | ,-ρφ hAT ^TWiT! ·* - H « | b | 1,19 | [M+HJ+: 1235 |
| 68 | b | 1,19- 130 | [M-H+HCO2HJ-: m/z 1123 (base peak)mixture of isomers |
| Compound | CHEMISTRY | LCSM | ||
| Méth | Tr | MS | ||
| 69 | a | 1,15 | [M+HJ+: 1243 | |
| 70 | a | I.I5 | [M+HJ+: 1243 | |
| 71 | a | I»23- 1.24 | [M+HJ+: 1354 mixture of isomers |
EXAMPLE 9: Compound 70 (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-2-((S)-1-(((2R,3Rl4R,5Rl6R)-5-hydroxy-3,45 dimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)-10-(((2S,3R,6R)-3-hydroxy4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,5l7,9,11,13-hexamethyl-7-(((2methyl-1-((phenylsulfonamido)propan-2-yl)carbamoyI)oxy)-6,14-dioxo-12-(((2S,5Rl7R)-
2,4,5-trimethyl-1,4-oxazepan-7-yl)oxy)oxacyclotetradecan-4-yl 3-methylbutanoate.
··
g of compound 1-a obtained in Example 1 are placed in pyridine (30 ml). Acetic anhydride (2.88 ml) is added. The mixture is stirred at room température for 40 hours. The resulting mixture is concentrated under vacuum, and extracted with 3 « 60 ml of DCM, washed with 40 ml of 1 M HCl, then with saturated aqueous NaHCÛ3 solution and finally with saturated NaCI solution. The organic phases are combined, dried over MgSO^, filtered and then evaporated to dryness. 3.5 g of the expected product are obtained in the form of a white powder.
MS: method e
Rétention time Tr (min) = 4.01; [M+H]*: 1073 ··
Step 9.2.a:
4.2 g of the compound prepared in step 9.1 are placed in DCM (150 ml). Pyridine (5.43 ml) is added and the mixture is cooled to O’C. Trichloromethyi chloroformate (diphosgene) (842.40 pl) is added and stirring is continued for 3 hours at O’C. 4Dimethylaminopyridine (507.03 mg) is added, the mixture is then allowed to warm to room température and stirring is continued ovemight. The resulting mixture Is evaporated to dryness under vacuum. The crude reaction product is used as obtained for the following stage.
Step 9.2.b: condensation of the amine
DMF (70 ml) is added to the crude reaction medium obtained in the above step. A dark brown suspension is obtained. TEA (4.91 ml) is added in a single portion, followed by N-(2-amino-2-methylpropyl)benzenesulfonamide hydrochloride (2.80 g) ln a single portion. The reaction mixture is stirred magnetically at room température for 24 hours. 400 ml of EtOAc are added. The mixture is washed with 200 ml of water and then with 200 ml of saturated aqueous NaCI solution. The aqueous phases are re-extracted with 400 ml of EtOAc. The organic phases are combined, dried over MgSO<, filtered through a sinter funnel and concentrated under reduced pressure. 8 g of a brown oil are recovered.
Step 9.2.c: deprotection of the alcohols
MeOH (40 ml) is added to the 8 g of brown oil obtained above. An orange solution is obtained. Potassium carbonate (1.30 g) is added in a single portion. The reaction mixture is stirred magnetically at room température for 2 hours 30 minutes. 150 ml of • ·
100
DCM are added. The mixture is washed with 75 ml of water and then with 75 ml of saturated aqueous NaCI solution. The aqueous phases are re-extracted with 150 ml of DCM. The organic phases are combined and then dried over MgSO4 and finally filtered through a sinter funnel. The filtrate is evaporated to dryness, and 3.5 g of an orange foam are recovered. The product Is purified by préparative HPLC under the following conditions:
• Apparatus: Waters 4000
Stationary phase: Kromasil C18 10 pm 300 x 50 mm • Mobile phase: B: 70/30 v/v acetonitrile/HîO +10 mM of ammonium acetate
Flow rate: 120 ml/min • UV détection: 210 nm · Cell length: 2.5 mm
After évaporation and lyophiiization, the following is obtained:
800 mg in the form of a yellow powder corresponding to the expected product.
MS: method b
Rétention time Tr (min) ® 1.15; [M+H]*: 1243
1H NMR spectrum (500MHz, in ppm, DMSO-de): 0.77 (d, J=6.6 Hz, 3 H); 0.88 to 0.97 (m, 12 H); 1.00 to 1.15 (m, 27 H); 1.62 to 1.82 (m, 4 H); 1.67 (s, 3 H); 1.90 to 2.05 (m, 4 H); 2.09 to 2.20 (m, 4 H); 2.19 (s, 3 H); 2.39 (dd, J=9.7 and 13.9 Hz, 1 H); 2.59 (m, 1 H); 2.68 to 2.79 (m, 3 H); 2.83 to 2.93 (m, 3 H); 2.98 (broad q, J=6.6 Hz, 1 H); 3.03 (m, 1 H); 3.30 (m, 1 H); 3.37 (s, 3 H); 3.45 (s, 3 H); 3.52 (m, 1 H); 3.59 to 3.69 (m, 3 H); 3.76 (broad d, J=4.1 Hz, 1 H); 3.80 (s, 3 H); 3.83 (m, 1 H); 3.88 (t, J=4.8 Hz, 1 H); 4.28 (m, 1 H); 4.45 (d, J=8.0 Hz, 1 H); 4.59 (d, J=9.9 Hz, 1 H); 4.68 (m, 2 H); 4.87 (d, J=7.1 Hz, 1 H); 4.91 (dd, J=2.6 and 9.2 Hz, 1 H); 5.27 (d, J=4.8 Hz, 1 H); 6.22 (s, 1 H); 7.51 (broad t, J=6.6 Hz, 1 H); 7.58 (t, J=7.5 Hz, 2 H); 7.63 (t, J=7.5 Hz. 1 H); 7.78 (d, J=7.5 Hz, 2 H).
EXAMPLE 10: Compound 72 (2R,3S,4R,5R,7S,9S,1 OS, 11 R,12S,13R)-10-{[(2S(3R,6R)-4-{[(1-{[(5R)-3-(3fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-1 /7-1,2,3-triazol-4-yl)methoxy]imino}-3hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7-hydroxy-2-(1-{[(2R,3R,4Rl5R,6R)-5hydroxy-3,4-dimethoxy-6-methyltetrahydro-2M-pyran-2-yl]oxy)propan-2-yl)-3,5,7,9,11,13hexamethyl-6,14-dioxo-12-{[(2S,5R,7R}-2,4,5-trimethyl-1(4-oxazepan-7yl]oxy)oxacyclotetradecan-4-yl 3-methylbutanoate.
< ·
200 mg of the compound obtained in Préparation 5 are placed in 2 ml of THF, the solution is cooled to 0°C and 172.51 mg of sodium metaperiodate dissolved in 2 ml of water are then added. The mixture is allowed to warm to room température, and stirring is continued for 4 hours. The precipitate is filtered off and rinsed with 0.5 ml of THF.
400 μΙ of a 2 M solution of methylamine in THF, then 46 μΙ of acetic acid and finally
63.5 mg of NaBHsCN are added to the filtrate. The suspension obtained is stirred at room température for 18 hours. The suspension is taken up in 40 ml of DCM. The mixture is washed with 20 ml of saturated aqueous NaHCOs solution and then with 20 ml of saturated aqueous NaCI solution. The organic phase is dried over MgSOi, filtered and finally concentrated under reduced pressure. The crude mixture is purified by chromatography on a Merck cartridge (10 g of 15*40 pm silica), eluting with a 92/8 CHCIs/MeOH mixture.
mg of the expected product and 5 mg of the other diastereoisomer are recovered.
MS: method b
ES-: [M-H+HCO2H]-: m/z 1293
1H NMR spectrum (500 MHz, In ppm, DMSO-d<): 0.79 (d, J=6.8 Hz, 3 H); 0.93 (d, J=6.8 Hz, 6 H); 0.95 to 1,00 (m, 9 H); 1.02 (d, J=6.6 Hz, 3 H); 1.05 to 1.14 (m, 15 H); 1.24 (s, 3 H); 1.48 (m, 1 H); 1.69 to 1.80 (m, 2 H); 1.83 to 2.07 (m, 6 H); 2.11 to
2.21 (m, 3 H); 2.17 (s, 3 H); 2.35 (dd, J=9.4 and 14.1 Hz, 1 H); 2.56 (m, 1 H); 2.69 (d, J=12.6 Hz, 1 H); 2.75 (m, 1 H); 2.83 (dd, J=3.0 and 16.5 H, 1 H); 2.92 (dd, J=2.6 and 7.9 Hz, 1 H); 3.03 (m, 1 H); 3.12 (broad q, J=6.8 Hz, 1 H); 3.30 (partially masked m, 1 H);
3.38 (s, 3 H); 3.45 (s, 3 H); 3.52 (m, 1 H); 3.59 to 3.73 (m, 4 H); 3.82 to 3.94 (m, 3 H);
4.22 to 4.28 (m, 2 H); 4.31 (s, 1 H); 4.45 (d, J=7.9 Hz, 1 H); 4.66 (d, J=9.7 Hz, 1 H); 4.68 (d, J=4.7 Hz, 1 H); 4.74 (d, J=9.4 Hz, 1 H); 4.82 (d, J=5.3 Hz, 2 H); 4.86 (d, J=7.2 Hz, 1 H); 4.91 (dd, J=3.1 and 9.4 Hz, 1 H); 5.11 (s, 2 H); 5.15 (m, 1 H); 5.30 (d, J=4.7 Hz, . *
102
H); 6.97 (dt, J=2.3 and 8.4 Hz, 1 H); 7.27 (dd, J=1.5 and 8.4 Hz, 1 H); 7.40 to 7.47 (m,
H); 8.21 (s, 1 H).
EXAMPLE 11 : Compound 88 ^R.aS^R.SRJS.gS.IOS.IIR.^S.ISR^-iiSJ-l-ÎÎ^R.SR^R.SR.eRj-S-hydroxy3,4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)-10-(((2S,3R,6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-7((methoxycarbonyl)oxy)-3,5l7l9l11,13-hexamethyl-6,14-dioxo-12-(((2Sl7R)-2,4,5trimethyl-1,4-oxazepan-7yl)oxy)oxacyclotetradecan-4-yl 3-methylbutanoate.
556 mg of the mixture of diastereoisomers obtained In Example 1 and 456 mg of Ν,Ν'-carbonyldiimidazole are placed in cyclohexane (3.3 ml). The mixture is heated at 100’C for 35 minutes by microwave. The heterogeneous medium Is taken up in 30 ml of DCM and washed with 20 ml of water and then with 20 ml of saturated NaCI solution. The aqueous phases are re-extracted with 30 ml of DCM. The organic phases are combined, dried over MgSOi, filtered and then evaporated to dryness under vacuum. 710 mg of the expected product are obtained.
103
MS: method a
Rétention time Tr (min) = 1.19; [M+H]*: 1271
1H NMR (in ppm, DMSOde) - Brüker spectrometer 0.79 (d, J=6.9 Hz, 3 H); 0.85 (d, J=7.1 Hz, 3 H); 0.90 to 0.95 (m, 12 H); 1.01 (d, J=6.9 Hz, 3 H); 1.06 to 1.14 (m, 9 H); 1.17 (d, J=6.3 Hz, 3 H); 1.25 (d, J=6.3 Hz, 3 H); 1.75 to 1.87 (m, 3 H); 1.92 (s, 3 H);
1.94 to 2.18 (m, 9 H); 2.20 (s, 3 H); 2.47 (m, 1 H); 2.65 to 2.81 (m, 3 H); 3.07 to 3.19 (m, 3 H); 3.37 (m, 1 H); 3.41 (s, 3 H); 3.44 (s, 3 H); 3.63 to 3.78 (m, 3 H); 3.72 (s, 3 H); 3.93 to 4.00 (m, 2 H); 4.10 to 4.17 (m, 2 H); 4.56 to 4.64 (m, 3 H); 4.69 (d, J=9.6 Hz, 1 H);
4.84 (m, 1 H); 5.00 (d, J=7.4 Hz, 1 H); 5.24 (d, J=7.4 Hz, 1 H); 7.10 (dd, J=0.8 and 1.6 Hz, 1 H); 7.12 (dd, J=0.8 and 1.6 Hz. 1 H); 7.15 (broad s, 1 H); 7.46 to 7.47 (t, J=1.6 Hz, 1 H);
7.62 (t, J=1.6 Hz, 1 H); 7.64 (t, J=1.6 Hz, 1 H); 8.12 (broad s, 1 H); 8.28 (broad s, 1 H);
8.30 (broad s, 1 H).
Step 11.2
500 mg of the compound isolated in step 11.1 are placed in THF (5 ml). 1 M hydrochloric acid (1.97 ml) is added. The mixture is stirred for 3 hours at room température. 50 ml of DCM are added and the resulting mixture is washed with saturated NaHCOa solution (20 ml) and then with saturated NaCI solution (20 ml). The aqueous phases are re-extracted with 50 ml of DCM. The organic phases are combined, dried over MgSO*, filtered and then evaporated to dryness under vacuum. 420 mg of the expected product are recovered.
MS: method a
Rétention time Tr (min) = 1.02; [M+H]*: 1083
104
mg of the compound prepared In step 11.2 are placed in MeOH (1 ml). Potassium carbonate (32.22 mg) is added and the mixture is stirred at room température for 4 hours. 15 ml of DCM are added and the mixture is washed with water and then with saturated NaCI solution. The aqueous phases are extracted with 15 mi of DCM. The organic phases are combined, dried over MgSO<, filtered and then evaporated to dryness under vacuum. 57 mg of a iacquer are obtained, which product is purified by chromatography on a Merck cartridge (2.5 g of 15-40 pm SiOH), eluting with a 97/3 EtOAc/TEA mixture. The fraction of Rf 0.35/0.45 (core fraction) is recovered, I.e. 14 mg of the expected compound.
MS: method a
Rétention time Tr (min) = 1.07; [M+H]*: 1047
1H NMR spectrum (500 MHz, in ppm, DMSO-de): 0.76 - 0.81 (m, 3 H); 0.89
- 0.94 (m, 6 H); 0.96 (d, J=6.6 Hz, 6 H); 0.99 - 1.17 (m, 21 H); 1.73 - 1.82 (m, 6 H); 1.85 (m, 1 H); 1.91 - 2.06 (m, 5 H); 2.11 - 2.21 (m, 6 H); 2.38 (dd, J=14.0, 9.6 Hz, 1 H); 2.53
- 2.66 (m, 1 H); 2.66 - 2.77 (m, 2 H); 2.81 - 2.89 (m, 1 H); 2.92 (dd, J=7.8, 2.6 Hz, 1 H); 2.98 - 3.06 (m, 2 H); 3.27 - 3.31 (masked m, 1 H); 3.38 (s, 3 H); 3.45 (s, 3 H); 3.48 - 3.56 (m, 1 H); 3.58 - 3.71 (m, 6 H); 3.74 - 3.78 (m, 1 H); 3.80 (s, 3 H); 3.82 - 3.92 (m, 2 H); 4.26 (d, J=6.3 Hz, 1 H); 4.45 (d, J=8.0 Hz, 1 H); 4.59 (d, J=10,2 Hz, 1 H); 4.63 - 4.75 (m, 2 H);
4.81 - 4.94 (m, 2 H); 5.29 - 5.34 (m, 1 H).
Table 2: Structures and analyses of compounds prepared according to one of the processes described In Examples 1 to 8 and 9 to 11 above.
105
| Compound | CHEMISTRY | LC MS | ||
| Meth. | Tr | MS | ||
| 73 | w- cp | f | 1.237 | [M+H]+: 1148.5 mixture of isomers |
| 74 | -yew | f | 1.12 | [M+HJ+: 1184.5 mixture of isomers |
| 75 | 0 H | h | 0.812 | [M+H]+: 1122.6 mixture of isomers |
| 76 | «>4- ~b | f | 1.209 | [M+HJ+: 1152.6 mixture of isomers |
| 77 | -ye+p- °λ | 9 | 0.881 | [M+H]+: 1083.3 mixture of isomers |
106
| Compound | CHEMISTRY | LCMS | ||
| Meth. | Tr | MS | ||
| 78 | W | b | 1.04 | [M+H]+: 1102 mixture of isomers |
| 79 | 'ÇC'^A V | f | 1.087 | [M+H1+: 1029.6 mixture of isomers |
| 80 | -«%ÿ- ? o / | f | 1.078 | [M+H1+: 1033.5 mixture of isomers |
| 81 | rp | f | 1.26 | [M+H]+: 1178.6 mixture of isomers |
| 82 | g | 0.899 | [M+H]+: 1095.5 mixture of isomers |
107
| Compound | CHEMISTRY | LCMS | |||
| Meth. | Tr | MS | |||
| 83 | ΑΧ73^· '-Q, | 9 | 1.026 | [M+H]+: 1083.7 mixture of isomers | |
| 84 | - Π « L / o-Η CH | b | 1.11 | [M+H]+: 1087 mixture of Isomers | |
| 85 | H | b | 1.13 | [M+H]+: 1031 mixture of Isomers | |
| 86 | 0 II Y t k V~ | o 1 OH | f | 1.139 | [M+H]+: 1190.8 mixture of isomers |
| 87 | . yjC Wç w b C -^--^ | ) > H | g | 0.63 | [M+H]+: 1200.4 |
108
| Compound | CHÈM1STRY | LCMS | |||
| Meth. | Tr | MS | |||
| 88 | w | -O 5 CH | b | 1.07 | [M+HJ+: 1047 mixture of isomers |
| 89 | ° Ύ l Sy ! | J M | 1 | 1.221 | [M+HJ+: 1074.7 |
| 90 | O « “ - /Jd ><7o-N O | p 0 | i | 1.017 | [M+2HJ/2+: 605 mixture of isomers |
| 91 | hcZ^o | f | 1.255 | [M+Na]+: 1152.7 mixture of isomers | |
| 92 | °x/ o 9 bVrn? | f | 1.272 | [M+HJ+: 1116.4 mixture of Isomers |
109
| Compound | CHEMISTRY | LCMS | ||||
| Meth. | Tr | MS | ||||
| 93 | °^r i H· XJ —0 O— 1 n rr | ο V5N r-r <T 1 | G O b 1 JH | b | 1.16 | [M+H]+: 1271 mixture of isomers |
| 94 | -- Tj » (J œ | b | 1.15 | [M+H]+: 1114 mixture of isomers | ||
| 95 | o O V5h ^?V | °,o M' ô 1 JH | b | 1.18 | [M+HJ+: 1283 | |
| 96 | ° i «4/τ.ΧΧ *- Λ [X>yJ | o V5* S 1 £ | --Cr^ | b | 1.18 | [M+HJ+: 1283 mixture of isomers |
| 97 | ^>SrV ° Ύ 1 TiIT —Ο Ο— ΐ crr | <T 1 | O Q 4 b ' JH | b | 1.14 | [M+H]+: 1313 mixture of isomers |
110
| Compound | CHEMISTRY | LCMS | |||
| Meth. | Tr | MS | |||
| 98 | WP 1 l | -0 o L | b | 1.18 | [M+H]+: 1283 |
| 99 | 0 y T WP /O-H C | M | i | 1.049 | [M+2H]/2+: 582.4 mixture of isomers |
| 100 | HCOCH ° « X. * Jt | Yl 1 0H | f | 1.336 | [M+2HJ/2+; 596.2 mixture of isomers |
| 101 | o o VT WV <W| X. | %· -« ô H | b | 1.21 | [M+H]+: 1299 |
| 102 | 0 0 V5* W | V Ô H | b | 1.22 | [M+H]+: 1283 mixture of Isomers |
| Compound | CHEMISTRY | LCMS | |||
| Meth. | Tr | MS | |||
| 103 | k * 0 WtY YWl J ” * HW | M | 1 | 1.045 | [M+2HJ/2+: 587.5 mixture of Isomers |
| 104 | T& | h | 0.889 | [M+2HJ/2+: 604 mixture of isomers | |
| 105 | . i î L· ί °Ί^1 4fàx~“ | i | 1.205 | [M+HJ+: 1279.6 mixture of Isomers | |
| 106 | 0 ? rH t | F . kjuXj^ o OH | 1 | 1.234 | [M+HJ+: 1311.6 mixture of isomers |
| 107 | O £ 0 ° 1 | CAtQ O F H | 1 | 1.176 | [M+H]+: 1261.6 mixture of isomers |
112
| Compound | CHEMISTRY | LCMS | |||
| Meth. | Tr | MS | |||
| 108 | 0 k 0 0 | y M û Γ 1 s 17, M | 1 | 1.224 | [M+HJ+: 1327.6 mixture of isomers |
| 109 | o k. P | i | 1.224 | [M+HJ+: 1327.6 mixture of isomers | |
| 110 | L xx | IH | 1 | 1.027 | [M+2HJ/2+: 580.4 mixture of isomers |
| 111 | XrXXpx xxi —o o— 1 2~CJ rH Vy0* X | h | 0.789 | [M+2HJ/2+: 604.2 mixture of isomers | |
| 112 | - H « t / O-N OH V' | a | 1.24 | [M+HJ+: 1284 mixture of isomers |
113
| Compound | CHEMISTRY | LCMS | ||
| Meth. | Tr | MS | ||
| 113 | eCm J (7 o-n œ | a | 1.2 | [M+HJ+: 1269 mixture of isomers |
| 114 | O O T y/ | a | 1.21 | (M+H]+: 1311 mixture of isomers |
| 115 | y --¾ | a | 1.19 | [M+H]+: 1257 |
| 116 | _ ί | i | 1.153 | (M+2HJ/2+: 659.4 mixture of isomers |
| 117 | C\^ //y ’ - aJq ou | g | 0 929 | [M+HJ+: 1311.8 mixture of isomers |
II4
| Compound | CHEMISTRY | LCMS | |||
| Meth. | Tr | MS | |||
| 118 | o 0 H Q | / ïï 0 mÛL I M | i | 1.194 | [M+HJ+: 1261.6 mixture of isomers |
| 119 | o ° -A-7/ | / M o F 3 M | i | 1.253 | [M+HJ+; 1279.6 mixture of isomers |
| 120 | 0 î \ A A | / N o F çô, . | f | 1.222 | [M+HJ+: 1297.6 mixture of isomers |
| 121 | « x U L· e a W. a - ·' r- P /·-· « A7 o A. | i | 1.169 | [M+HJ+: 1312.7 mixture of isomers | |
| 122 | G HAY^T- ° *Ύ 1 ffœc~ 0 | g | 0.932 | [M+H]+: 1079.5 mixture of isomers |
115
| Compound | CHEMISTRY | LCMS | |||
| Meth. | Tr | MS | |||
| 123 | O | ~o 0 CH | h | 0.975 | [M+HJ+: 1094.6 mixture of isomers |
| 124 | A-$Âî Ύ V KïïA | 1 | f | 1.16 | [M+H]+: 1057.6 mixture of isomers |
| 125 | Ve Xk ° x^j d | ) Ή | 9 | 0.823 | [M+H]+: 1065.6 mixture of isomers |
| 126 | o ό^Λ- ° Ή τ ho-(7 σΑΆ -X v b > n w AA/m | 5 >1 | f | 1.215 | [M+H]+: 1045.7 mixture of isomers |
| 127 | ApW- | 3 M | f | 1.197 | [M+H]+: 1003.5 mixture of isomers |
ll6
| Compound | CHEMISTRY | LCMS | |||
| Meth. | Tr | MS | |||
| 128 | O c7' | ) DH | h | 0.93 | [M+H]+: 1043.8 mixture of isomère |
| 129 | ^Vî7| M J1 /o-N C c7 | H | h | 0.971 | [M+HJ+: 1059.7 mixture of isomers |
| 130 | K t □7” | -0 O \x | h | 0.852 | [M+HJ+: 1029.5 mixture of isomère |
| 131 | Wç '7 J P <A°7~ | h | 0.884 | [M+HJ+: 1150.6 mixture of isomère | |
| 132 | < | g | 0.886 | [M+HJ+: 1016.6 mixture of Isomère |
117
| Compound | CHEMISTRY | LCMS | |||
| Meth. | Tr | MS | |||
| 133 | > Ή | f | 1.275 | [M+H]+: 1107.7 mixture of Isomers | |
| 134 | 3 | f | 1.224 | [M+H]+; 1031.7 mixture of isomers | |
| 135 | T 1 | 3 □i | f | 1.247 | [M+H]+: 1045.6 mixture of isomers |
| 136 | priw tjjif | Ό CH | f | 1.253 | [M+HJ+: 1186.5 mixture of Isomers |
| 137 | < | h | 1.039 | [M+H]+: 1045 6 mixture of isomers |
118
| Compound | CHEMISTRY | LCMS | ||
| Meth. | Tr | MS | ||
| 138 | Λ | f | 1.219 | [M+H]+: 1017.6 mixture of isomers |
[USES]
The compounds correspondîng to the general formula (I) that are the subject of the invention underwent microbiological trials which showed their value as therapeuticaiiy active substances. Specifically, they hâve bacteriostatic and/or bactericidal action on mycobacteria, especially against strains of Mycobacterium or Corynebacterium, which are in particular sensitive and résistant to the first-line antibiotics.
The compounds correspondîng to the general formula (I) which are the subject of the invention also hâve bacteriostatic and/or bactericidal action on gram-positive microorganisms, in particular on staphylococci and streptococci.
More precisely, the compounds correspondîng to the general formula (I) which are the subject of the Invention are used for the prévention and/or treatment of bacterial 15 Infections caused by mycobacteria and gram-positive microorganisms.
Measurement of the Inhlbitory activity (ICeo) of the compounds according to the invention towards Streptococcus pneumoniae
Materials and methods
The test used is a bioluminescence test, the aim of which Is to measure the Inhibition of bacterial growth of Streptococcus pneumoniae by quantification of the amount of adenosine triphosphate (ATP). Specifically, ATP Is a major and mandatory energy 25 intermediate of very many réactions of cell metabolism which characterizes live media.
ATP quantification is performed at the end of the test by using an enzyme, luciferase, which, in the presence of ATP and of a spécifie substrate, luciferin, produces quantifiable light.
119
Thus, In the presence of luciferin and luciferase at non-saturating concentrations, the value obtained in relative light units (RLU) will make it possible, by means of a calibration, to estimate the amount of ATP and thus deduce the number of live bacteria at the end of the incubation period.
Thus, the more the RLU value obtained at the end of the test tends towards zéro, the more the product inhibits the total growth of bacteria.
The results (Table 3) are expressed in ICeo. The ICeo corresponds to 80% inhibition of the bacterial growth of S. pneumoniae with, as reference antibiotic, vancomycin, which has an ICeo of 0.14 μΜ.
The experiments performed demonstrate that the compounds according to the présent invention hâve activity on inhibiting the growth of S. pneumoniae. The ICeo values are typically between 0.1 and 10 μΜ, or even between 0.1 and 1 μΜ.
Measurement of the Inhibitory activity of the compounds according to the invention towards Mycobacterium tuberculosls
The in vitro test used makes it possible to identify molécules having antimicrobial activity on the strain of Mycobacterium tuberculose H37Rv. This is a bacterium of biohazard category 3.
Materials and methods
The test used is Alamar blue (MABA). This is a colorimétrie test which makes it possible to détermine the MIC (minimum inhibitory concentration) of antibacterial agents. Alamar blue is a redox Indicator which changes from blue to pink in the case of bacterial growth. Resazurin (blue and non-fluorescent) is reduced to resorufin (pink and fluorescent) by live bacteria. The plate is thus read visually or by fluorescence measurement. The fluorescence intensity is proportional to the number of live bacteria.
Thus, the more the fluorimetric MIC value tends towards zéro, the less the amount of product necessary to inhibit the total growth of the bacteria.
The experiments performed demonstrate that the compounds according to the présent invention hâve activity on inhibiting the growth of M. tuberculosis. The MIC values
I20 are typically between 0.1 and 10 μΜ, or even between 0,1 and 1 μΜ. The compounds presented as examples in the présent patent application generally hâve MIC values of less than 1 μΜ.
Table 3: Table of activities
| Activities | ||
| Coumpounds | MIC (μΜ) MTb H37Rv | IC80 (μΜ) S. pneumoniae |
| 11 | 0.63 | ND |
| 12 | 0.6 | ND |
| 7-b | 0.52 | ND |
| 7-a | 0.54 | ND |
| 14 | 0.67 | 2.27 |
| 8-a | 0.56 | 1.84 |
| 2 | 1.25 | 0.28 |
| 24 | 0.48 | 0.88 |
| 25 | 0.42 | 2.03 |
| 26 | 0.78 | 0.69 |
| 33 | 0.35 | 1.34 |
| 35 | 0.36 | 1.81 |
| 36 | 0.49 | ND |
| 37 | 0.59 | 1.88 |
| 3 | 1.27 | ND |
| 6 | 0.91 | ND |
| 51 | 0.29 | ND |
| 4 | 0.21 | ND |
| 1-a | 2.05 | ND |
| 5-a | 0.34 | ND |
| 5-b | 0.53 | ND |
| 70 | 0.46 | ND |
ND: not determined.
The compounds according to the invention, namely the compounds corresponding to formula (I), furthermore hâve good microbiological properties and are particularly suitable for use in preparing médicaments, in particular narrow-spectrum antibiotics for 15 treating and/or preventing tuberculosis.
In particular, these antibiotics hâve antimicrobial action against M. tuberculosis for the treatment and/or prévention of tuberculosis.
121
Thus, according to another of its aspects, a subject of the invention is médicaments that comprise a compound of formula (I), or an addition sait thereof with a pharmaceutically acceptable acid or base ofthe compound of formula (I).
These médicaments find their use in therapeutics, especially in the treatment and/or prévention oftuberculosis.
According to another of its aspects, the présent invention relates to pharmaceutical compositions comprising, as active ingrédient, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable sait of the said compound, and also at least one pharmaceutically acceptable excipient.
The said excipients are chosen, according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
In the pharmaceutical compositions of the présent invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or the sait thereof, may be administered in unit administration form, as a mixture with standard pharmaceutical excipients, to man and animais for the prévention or treatment of the above disorders or diseases.
The appropriate unit administration forms include oral forms, such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, Intratracheal, intraocular and intranasal administration forms, forms of administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms, and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.
By way of example, a unit administration form of a compound according to the invention in tablet form may comprise the following constituents:
122
Compound according to the invention Mannitol
Croscaramellose sodium
Com starch
Hydroxypropylmethylcellulose Magnésium stéarate
50.0 mg
223.75 mg
6.0 mg 15.0 mg
2.25 mg
3.0 mg
There may be particular cases where higher or lower dosages are appropriate; such dosages do not départ from the context of the invention. According to the usual practice, the dosage appropriate for each patient is determined by the physician according to the method of administration and the weight and response of the said patient.
According to another of its aspects, the présent invention relates to the use of the compounds of formula (I) for the prévention and/or treatment of bacterial infections caused by gram-positive microorganisms and mycobacteria.
According to another of its aspects, the présent invention also relates to the use of the compounds of formula (I), or a pharmaceutically acceptable sait thereof, for the treatment and/or prévention of bacterial infections caused by mycobacteria such as M. tuberculosis, M. smegmatis, M. phlei, or other microorganisms such as Nocardia brasiliensis, Nocardia absessus or Corynebacterium diphtheria, for example.
Thus, one of the aspects of the invention concems the use of the compounds of formula (I), or a pharmaceutically acceptable sait thereof, for the treatment and/or prévention of infectious diseases such as tuberculosis, leprosy, nocardiosis, diphtheria, pulmonary mycobacterial infection, cutaneous mycobacterial infection, atypic mycobacterial infection and mycobacteriosis.
The term tuberculosis includes infections caused by bacilli of the tuberculosis complex (M. tuberculosis, M. bovis and M. africanum) that are ail pathogenic to man. Pulmonary tuberculosis is far and away the most frequent and the most widespread; this is tuberculosis of the lung, of the larynx, of the trachea and of the bronchi, tuberculosis of the intrathoracic lymphatic ganglions, pleural respiratory tuberculosis, primary respiratory tuberculosis and any other respiratory tuberculosis. Although less frequent, ganglionic tuberculosis and extrapulmonary tuberculosis, tuberculosis of the nervous system such as tuberculous meningitis. tuberculous leptomeningitis, cérébral tuberculomes and any other
123 tuberculosis of the nervous System, or bone or joint tuberculosïs, tuberculosis of the urogénital System, lymphadenopathic peripheral tuberculosis, intestinal tuberculosis, peritoneal tuberculosis and/or tuberculosis of the mesenteric glands, cutaneous tuberculosis and tuberculosis of the subcutaneous tissues, tuberculosis of the eye, of the ear or ofthe adrenal glands, and dïsseminated tuberculosis, also exïst.
The term leprosy (Hansen's disease) includes infections caused by Mycobacterium leprae: indeterminate leprosy, tuberculoid leprosy, borderiine leprosy, borderline tuberculoid leprosy, lepromatous leprosy, and also the other forms of leprosy.
The term diphtheria includes pharyngeal diphtheria, nasopharyngeal diphtheria, cutaneous diphtheria, and also the other forms of diphtheria.
The term nocardiosis includes pulmonary nocardiosis, cutaneous nocardiosis, and the other forms of nocardiosis.
According to another of its aspects, the présent invention also relates to a method for treating the pathologies indicated above, which comprises the administration, to a patient, of an effective dose of a compound of formula (I).
Claims (14)
1. Compound of formula (I):
o in which:
- Y représente a hydrogen atom, a group -(C=O)-NR2R3 or a group -(C=O)-O-Rie;
- Z represents:
• a hydrogen atom, • a group -Ci_6-alkyl. which is unsubstituted or substituted with one or more groups R4, • a group -C3-7-cycloalkyl, which is unsubstituted or substituted with a group -NH-(C=O)-Rw or with a group -NH-SO2-R20.
• a group -C3-6-heterocycloalkyl, • a group -NH-(C=O)-R5;
- Ri represents a hydrogen atom, a group -C2-6-alkenyl, a group -C2-e-alkynyl or a group -Ci-6-alkyl which is unsubstituted or substituted with a group -C1-4fluoroalkyl or with a heteroaryl group which is unsubstituted or substituted with a group 3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-ylmethyl;
- R2 represents a hydrogen atom or a group -Ci-e-alkyl;
- R3 represents:
• a group -C3-7-cycloalkyl, which is unsubstituted or substituted with a group -Ct-3-alkyl substituted with a group -NH-SO2-R21, • ·
125 • a heteroaryl group, • a linear or branched group -Ci-e-alkyl, which is unsubstituted or substituted with a group chosen from:
• a group -NH-Re, • a group -NH-SO2-R7, • a group -NH-(C=O)-R8.
• a group -C3-7-cycloalkyl, which is unsubstituted or substituted with a group -C3-6-heterocycloalkyl, • a group -C3_6-heterocycloalkyl, • an aryl group, which is unsubstituted or substituted with one or more groups chosen independently from a halogen atom and a group -CM-fluoroalkyl, • a heteroaryl group, which is unsubstituted or substituted with a group -Ci.3-alkyl, a group -CM-alkoxy, a group -CM-fluoroalkyl or a group -C3-e-heterocycloalkyl, • or altematively with one or more groups -CM-alkoxy;
or altematively R2 and R3, together with the nitrogen atom to which they are attached, constitute a group -C3-6-heterocycloalkyl chosen from: aziridine, azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine; the said heterocycloalkyl group being unsubstituted or substituted with a heteroaryl group, the said heteroaryl group being unsubstituted or substituted with a group CM-fluoroalkyl;
R4 independently represents a group chosen from:
• a hydroxyl group, • a deuterium, • a halogen atom, • a group -C3-7-cycloalkyl, • an aryl group, which Is unsubstituted or substituted with one or more groups -Rs,
126 • a heteroaryl group, • a group -C3-6-heterocycloalkyl, • a group -Ci-4-alkoxy, • a group -(C=0)-NH-Rio, • a group-NH-Rti, • a group -NH-(C=O)-Ri2, • oragroup-NH(SOi3)-Ri3;
- Rs represents a heteroaryl group;
- Re represents a heteroaryl group, which is unsubstituted or substituted with one or more halogen atoms;
- R7 represents a group -Ci-4-fluoroalkyl, an aryl group or a heteroaryl group, the said aryl and heteroaryl groups being unsubstituted or substituted with one or more groups Rr;
- Re represents a heteroaryl group, which Is unsubstituted or substituted with one or more groups Rz;
- Rg represents a halogen atom, a group -CM-alkoxy, a formyl group (CHO) or a group -C-M-alkyl, which is unsubstituted or substituted with a hydroxyl group;
- Rio represents a heteroaryl group, which is unsubstituted or substituted with a group -Ci-3-alkyl;
- R11 represents:
• a group -C3-io-heterocycloalkyl, which is unsubstituted or substituted with one or more oxide groups, • a heteroaryl group or an aryl-CM-alkyl group, the said heteroaryl or aryl groups being unsubstituted or substituted with one or more groups independently chosen from a halogen atom, a hydroxyl group, a nitro group and a group -Ci-3-alkyl;
127
- R12 represents:
• a group -Ci-4-alkoxy, • a group -Ci-4-alkyl, which Is unsubstituted or substîtuted with a group -NR14R15 or with a heteroaryl group, the said heteroaryl group being unsubstituted or substîtuted with a group -Ci-3-alkyl, • a heteroaryl group, which is unsubstituted or substîtuted with one or more groups chosen from a hydroxyl group and a group -Ci-3-alkyl;
- R13 represents:
• a group -Ci-4-alkyl, • a group -Ci-4-fluoroalkyl, • an aryl group, which is unsubstituted or substîtuted with a nitro group, • or a heteroaryl group, which is unsubstituted or substîtuted with a group -NR16R17;
- R14, R15, Rie and R17 each independently represent:
• a hydrogen atom, • or a group -Ci-4-alkyl;
- Rie represents a group -CM-alkyl or a benzyl group;
- R19 represents an aryl group or a heteroaryl group;
- R20 represents a group -CM-alkyl or an aryl group;
- R21 represents an aryl group;
- Rr represents:
• a halogen atom, • a group -Ci-4-alkoxy, • a group -Ci^-fluoroalkyl, • a group -OCF3, • a nitro group, • a group -NH2,
128 • a group -NHCH3;
- R? represents:
• a hydroxyl group, • a group -Ci-e-alkyL
2. Compound according to Claim 1, of formula (IA):
in which:
10 - R1.R2.R3 and Z are as defined in Claim 1.
3. Compound according to Claim 1, of formula (IB): o in which:
Ri and Z are as defined in Claim 1.
.·
129
Ri, Ris and Z are as defined in Claim 1.
5. Compound of formula (I) according to Claim 1, characterized In that:
- Y represents a hydrogen atom, a group -(C=O)-NR2R3 or a group -(C=O)-OMe;
- Z represents:
• a hydrogen atom, • a group -Ci-e-alkyl, which ls unsubstituted or substituted with one or more groups R4.
• a cyclopropyl group, a cyclobutyl group, a 3-(benzoylamino)cyclobutyl group, a 3-[(pyrazin-2-ylcarbonyl)amino]cyclobutyl group, a 3[(methylsulfonyl)amino]cyclobutyl group, a 3[(phenylsulfonyl)amino]cyclobutyl group, a cyclopentyl group, a cyclohexyl group, • a tetrahydro-2H-pyranyl group, • a group -NH-(C=O)-Rs;
- Ri represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethyl group or a methyl group, which is unsubstituted or substituted with a 1.2.3-triazole group substituted with a 3-(3-fluorophenyl)-2-oxo-1.3-oxazolidin-5-ylmethyl group:
- R2 represents a hydrogen atom or a methyl group;
l·
130
- R3 represents:
• a cyclohexyl group, a 1-{[(phenylsulfonyl)amino]methyl}cyclohexyl group or a 1-{[(phenylsulfonyl)aminojmethyl}cyclopentyl group, • a 5,6,7,8-tetrahydroquÎnolin-5-yl group, • or a linear or branched group CM-alkyl, which is unsubstituted or substituted with a group chosen from:
• -NH-Re, • -NH-SO2-R7, • -NH-(C=O)-Ra, • a 1-morpholin-4-ylcyclopentyl group, • a tetrahydro-2H-pyranyl group, a tetrahydrofuranyl group or a morpholin-4-yl group, • a phenyl group, which is unsubstituted or substituted with one or more groups chosen independently from a chlorine atom and a group -CF3, • a 1H-pynOlo[2,3-b]pyridinyl group, a 4-methyl-5,6,7,8- tetrahydroquinazolin-2-yl group, a 6-methoxy-1 H-benzimidazol-2-yl group, a pyridinyl group, which is unsubstituted or substituted with a group -CF3 or with a morpholin-4-yl group, • or altematively with one or more methoxy groups;
- or altematively R2 and R3, together with the nitrogen atom to which they are attached, constitute a -C3-6-heterocycloalkyl group chosen from: azetidine, morpholine, 4-[5-(trifluoromethyl)pyridin-2-yl]piperazine;
- R4 independently represents a group chosen from:
• a hydroxyl group, • a deuterium, • a fluorine atom, • a cyclopropyl group, «
b1
131 • a phenyl group, which is unsubstituted or substituted with one or more groups chosen independently from a fluorine atom, a methoxy group, a CH2OH group and a -CHO group, • a pyridyl group, • a morpholinyl group, a tetrahydro-2H-pyranyl group, • a methoxy group, • a group -(C=0)-NH-Rio, • agroup-NH-Rn, • a group -NH-(C=O)-Ri2, • oragroup-NH(S02)-Ri3;
- Rs represents a pyridyl group;
- Re represents a quinolyl group, the said quinolyl group being unsubstituted or substituted with a chlorine atom;
- R7 represents a -CF3 group, a phenyl, pyridyl, pyrazolyl, 1 H-pyrrolo[2,3-b]pyridyl or indolyl group, the said phenyl, pyridyl, pyrazolyl, 1H-pyrrolo[2,3-b]pyridyl or Indolyl groups being unsubstituted or substituted with one or more groups Rr;
- Re represents a pyrazinyl group, the said pyrazinyl group being unsubstituted or substituted with one or more groups R?;
- R10 represents a 1,8-naphthyridinyl group substituted with a methyl group;
- R11 represents a tetrahydrothiophene-1,1 -dioxide, quinolyl, pyridyl or benzyl group, the said quinolyl, pyridyl or benzyl groups being unsubstituted or substituted with a chlorine atom, a hydroxyl group, a nitro group or a methyl group;
- R12 represents:
• a tert-butoxy group, • a group -CM-alkyl, which is unsubstituted or substituted with a group chosen from a group -NR14R15, pyridyl or pyrazolyl, the said pyridyl or pyrazolyl groups being unsubstituted or substituted with a methyl group, • a pyrazinyl or pyridyl, which is unsubstituted or substituted with one or more groups chosen from a hydroxyl group and a methyl group;
132
- Ru represents:
• a group -CF3, • a phenyl group, which is unsubstituted or substituted with a nitro group, • or a pyridyl group, which is unsubstituted or substituted with a group -NR16R17;
- Ri4, Ris, R16 and R17 each independently represent:
• a hydrogen atom, • a methyl group or an isopropyl group;
• Rr represents:
• a fluorine atom, a chlorine atom, • a methoxy group, • a group -CF3, • a group -OCF3, • a nitro group, • a group -NH2, • a group -NHCH3;
- Rz represents:
• a hydroxyl group, • a methyl group.
6. Compound of formula (I) according to Claim 1, characterized In that:
- Y represents a hydrogen atom or a group -(C=O)-NR2R3!
- Z represents:
• a hydrogen atom, • a methyl group, an isopropyl group, a 2,2-dimethylpropyl group, • a group CD3, • a 2-fluoroethyl group, • a cyclopropylmethyl group,
133 • a 2-pheny!ethy! group, • a [(7- methyl-1,8-naphthyridin-2-yl)amino]-4-oxobutyl group, • a 2-{[(2-nitrophenyl)sulfony!]amino}ethy! group, • a cyclopropyl group, • a tetrahydro-2H-pyranyl group;
- Rt represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethy! group or a methyl group;
- R2 represents a hydrogen atom or a methyl group;
- R3 represents:
• a methyl group, • a 24[(2,6-difluorophenyl)sulfony!]amino}-1,1-dimethylethyl group, • a 1,1-dimethyl-2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethy! group, • a 2-{[(2-fluorophenyl)sulfonyl]amino}-1,1-dimethylethyl group, • a 1,1-dimethyl-2-({[2-(trifluoromethoxy)pheny!]su!fonyl)amino)ethy! group, • a 1,1-dimethyl-2-({[4-(trifluoromethoxy)phenyl]su!fony!}amino)ethyl group, • a 2-methy!-1-[(phenylsulfonyl)amino]propan-2-y! group, • a 2-methy!-1 -{[(5-nitro-1 H-pyrazol-4-y!)sulfony!]amino}propan-2-y! group, • a 2-methyl-1-{[(trifluoromethyl)sulfony!]amino}propan-2-yl group, • a 2-methyl-1-{[(2-nitrophenyl)su!fonyl]amino}propan-2-yl group, • a 1-{[(5-hydroxypyrazin-2-yl)carbonyl]amino}-2-methylpropan-2-y! group, • a 1,1-dimethyl-2-morpholin-4-ylethyl group, • a benzyl group, • a 2-(4-pyridyl)ethy! group.
7. Compound of formula (I) according to any one of Claims 1 to 6, characterized in that it corresponds to the following compounds:
• (2R,3S,4RI5R,7SI9S, 10S, 11 R, 12S, 13R)-7-[(benzylcarbamoyl)oxy]-2-(1 {[(2R13R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-y!)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6methy!tetrahydro-2H-pyran-2-y!]oxy}-315,7,9,11,13-hexamethyl-6,14-dioxo-12..17212
134 {[(2S(5S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S,9S,1 OS, 11 R,12S,13R)-7-[(benzylcafbamoyl)oxy]-2(1{[(2R,3R(4R,5Rl6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-
2- yl]oxy}propan-2-yl)-10-([(2Sl3Rl6R)-3-hydroxy-4-(methoxyimÎno)-6methyltetrahydro-2H-pyran-2-yl]oxy}-3,5(7,9,11,13-hexamethyl-6,14-dtoxo-12([(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-{[(2S,7R)-4-cyclopropyl-2,5dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4Rl5Rl6R)-5-hydroxy-3l4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-([(2S,3R,6R)-
3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7-{[(1-{[(5hydroxypyrazin-2-yl)carbonyl]amino}-2-methylpropan-2-yl)carbamoyl]oxy}-
3,5,7,9,11,13-hexamethy 1-6,14-dioxooxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12{[(2S,5R,7R)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R(3R,4Rl5R,6R)-5hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2ylloxyJ-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11 R,12S, 13R)-2-(1 -{[(2R,3R,4R,5R16R)-5-hydroxy-
3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2yl]oxy}-3(5,7,9,11,13-hexamethyl-6,14-dioxo-7-(([2-(pyridin-4yl)ethyl]carbamoyl}oxy)-12-{[(2S,5S,7R)-2,4,5-trimethyl-1,4-oxazepan-7yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
• ^R.SS^R.SR.ÎS.gS.IOS.I1R.12S, 13R)-7-[(benzylcarbamoyl)oxy]-12{[(2S,7R)-4-cyclopropyl-2,5-dîmethyl-1,4-oxazepan-7-yl]oxy}-2-(1{[(2R,3R,4R(5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-yl)-104[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6methyltetrahydro-2H-pyran-2-yl]oxy)-3,5,7,9,11,13-hexamethyl-6,14dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12{[(2S,7R)-2,5-dimethyl-4-(2H3)methyl-1,4-oxazepan-7-yl]oxy}-2-(1{[(2R,3R,4R,5R(6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-217212
135 yl]oxy}propan-2-yl)-10-{K2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6methyltetrahydro-2H-pyran-2-yl]oxy}-3,5.7,9.11,13-hexamethyl-6,14dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(dimethylcarbamoyl)oxy]-2-(1{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12{[(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R.3S.4R.5R.7S.9S.1 OS, 11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12{[(2S,7R)-2,5-dimethyl-4-(2-([(2-nitrophenyl)sulfonyl]amino}ethyl)-1,4oxazepan-7-yl]oxy}-2-(1-(I(2Rl3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6methyltetrahydro-2H-pyran-2-yl]oxy]propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,1 OS, 11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12- {[( 2S,7R)-4-(2-fïuoroethy!)-2,5-di methyl-1,4-oxazepan-7-yl]oxy}-2-(1 {[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,1 OS, 11 R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12{[(2S,7R)-2,5-dimethyl-4-(4-[(7-methyl-1,8-naphthyridin-2-yl)amino]-4oxobutyl}-1,4-oxazepan-7-yl]oxy}-2-(1-([(2R,3R,4Rl5R,6R)-5-hydroxy-3,4dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-([(2S,3R,6R)3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-
3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S,9S, 10S, 11 R, 12S, 13R)-7-[(benzylcarbamoyl)oxy]-12{[(2S,7R)-4(2,2-dimethylpropyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}propan-2-yl)-10-([(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,1 OS, 11 R,12S.13R)-12-([(2S,7R)-2,5-dimethyl-4-(2phenylethyl)-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4Rl5R,6R)-5-hydroxy-3l4 t
136 dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S13Rl6R)3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7-{[(1-{[(5hydroxypyrazin-2-yl)carbonyl]amino}-2-methylpropan-2-yl)carbamoyl]oxy}-
3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11 R, 12S,13R)-2-(1 -fl(2R,3R,4R,5R,6R)-5-hydroxy-
3.4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10{[(2S, 3R, 6R)-3-hydroxy-4-(methoxyi mino)-6-methyltetrahydro-2H-pyran-2ylIoxyJ-S.SJ.g.ll.ia-hexamethyl-T-fl^-methyl-l-fltS-nitro-IH-pyrazoMyl)sulfonyl]amino}propan-2-yl)carbamoyl]oxy}-6,14-dioxo-12-{[(2S,7R)-2l4,5trimethy 1-1,4-oxazepa n-7-yl]oxy}oxacyclotetradeca n-4-yI 3-methyl butanoate ;
• (2R,3S,4R,5R,7S,9Sl10S,1lR,12S,13R)-7-hydroxy-2-(1-{[(2R,3Rl4R,5R,6R)-
5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,5RI7R)-2,415-trimethyl-
1.4- oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S, 1OS, 11 R, 12S, 13R)-2-(1 -fl(2R,3R,4R,5R,6R)-5-hydroxy-
3.4- dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2yl]oxyJ-3,5,7,9,11,13-hexamethyl-7-{[(2-methyl-1 {[(trifluoromethyl)sulfonyl]amino}propan-2-yl)carbamoyl]oxy}-6,14-dioxo-12{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11 R, 12S,13R)-12-fl(2S,7R)-2,5-dimethyl-4-(2phenylethyl)-1,4-oxazepan-7-yl]oxy}-7-hydroxy-2-(1-{[(2R,3R,4R,5Rl6R)-5hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2yl]oxy}-3,5,7,9,11I13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S,9S,1 OS, 11 R, 12S,13R)-2-(1 -fl(2R,3R,4R,5R,6R)-5-hydroxy-
3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2yl]oxy}-3,5,7,9,11,13-hexamethyl-7-{[(2-methyl-1-{[(2nitrophenyl)sulfonyl]amino}propan-2-yl)carbamoyl]oxy}-6,14-dioxo-12{[(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
*
137 • (2R,3S,4R,5Rl7Sl9Sl10S,11R,12S,13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-
3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2yl]oxy}-3,5,7,9,11,13-hexamethyl-7-{[(2-methyl-1-{[(2nitropheny1)sulfony1]amino}propan-2-yl)carbamoyl]oxy}-6l14-dioxo-12{[(2S,5Sl7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10Sl11R,12Sl13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-
3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2yljoxy )-3,5,7,9,11,13-hexamethyl-7-[({2-methyl-1- [(phenylsulfonyl)amino]propan-2-yl}carbamoyl)oxy]-6,14-dioxo-12{[(2S,5S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S, 9S.10S.11R.12S, 13R)-2-(1-{[(2R, 3R.4R, 5R,6R)-5-hydroxy-
3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2yl]oxy}-3,5,7,9,11,13-hexamethyl-7-[({2-methyl-1[(phenylsulfonyl)amino]propan-2-yl}carbamoyl)oxy]-6,14-dioxo-12{[(2Sl5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy)oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11 R,12S, 13 R)-7-[({ 1,1 -dimethyl-2[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R,6R)-5hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-rnethylethyl)10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2yl] oxy }-12-{[(2S,7R)-4-isopropyl-2,5-dÎmethyl-1,4-oxazepan-7-yl]oxy}-
3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4Rl5R,7S,9S,10S,11R,12S,13R)-12-{[(2S,5R,7RM(cyclopropylmethyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-7-[({1,1-dimethyl-2[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3 R,4 R, 5R,6 R)-5hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)10-i[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2yl]oxy}-3,5,7,9l11,13-hexamethyl-6l14-dioxooxacyclotetradecan-4-yl 3methylbutanoate;
138 • (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-{[(2S,7RH-(cyclopropylmethyl)-
2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-7-[({1,1-dimethyl-2[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R14R,5R,6R)-5hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2ylJoxyJ-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacydotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[({1 .l-dimethyl^[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-{[(2Sl7R)-2,5-dimethyl-4(tetrahydro-2H-pyran-4-yl)-1,4-oxazepan-7-yl]oxy}-2-(2-{[(2R)3R,4R,5R(6R)-5hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2ylloxyJ-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacydotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R,7S.9S.1 OS, 11 R,12S, 13R)-12-{[(2S,5S,7R)-4(cydopropylmethyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-7-[((1,1 -dimethyl-2[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R15R,6R)-5hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacydotetradecan-4-yl 3methylbutanoate;
• ÆR.SS^R.SRJS.gS.I OS, 11 R,12S,13R)-7-[ ({1,1 -dimethyl-2[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-{[(2Sl5R,7R)-4-(2l2dimethylpropyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(2-{I(2R,3R,4Rl5R,6R)-
5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro2H-pyran-2-y1]oxy}-3,5,7,9l11,13-hexamethy1-6l14-dioxooxacydotetradecan-4yl 3-methylbutanoate;
• (2^38^,5^78,98,10S,11 R, 12S, 13R)-7-{({1,1 -dimethyl-2[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-{[(2S,7R)-4-(2,2dimethylpropyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(2-{[(2R,3Rl4R,5R,6R)-
5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro2H-pyra n-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacydotetradecan-4yl 3-methylbutanoate;
• «
139 • (2R,3S,4R,5R,7S,9S,10S.11 R.12S.13R)-7-{[< 1,1-dimethyl-2-morpholin-4ylethyl)carbamoylIoxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6methyltetrahydro-2H-pyran-2-yl]oxy}-1 -methylethyl)-10-i[(2S,3R,6R)-3hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-
3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2Sl7R)-2,4(5-trimethyl-1,4oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-{[(2-{[(2,6difluorophenyl)sulfonyllamino}-1,1-dimethylethyl)carbamoylIoxy}-2-(2([(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl] oxy}-1 -methylethyl)-10-{[(2S, 3R,6R)-3-hydroxy-4-(methoxyimino)-6methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R,3S,4R,5R, 7S, 9S,10S,11R,12S, 13R)-7-({[1,1-dimethyl-2-({[4(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamoyl}oxy)-2-(2{[(2R13R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}-1-methylethyl)-10-{I(2S,3Rl6R)-3-hydroxy-4-(methoxyÎmino)-6methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R, 3S,4R,5R,7S, 9S, 10S, 11 R, 12S, 13R)-7-{[(2-{[(2fluorophenyl)sulfonyl]amino}-1,1-dimethylethyl)carbamoyl]oxy}-2-(2{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yl]oxy}-1 -methylethyl)-10-{[(2S,3R,6R)-3-hydroxy^-(methoxyimino)-6methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R, 3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-({[1,1 -dimethyl-2-({[2(trifluoromethoxy)phenyl]sulfonyl}amino)ethylIcarbamoyl}oxy)-2-(2{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2y I] oxy }-1 -methylethyl)-10-{[(2S, 3R,6R)-3-hydroxy-4-(methoxyimino)-6methyltetrahydro-2H-pyran-2-yl]oxy)-3l5l7l9,11,13-hexamethyl-6,14-dioxo-12{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
140 • (2R,3S,4R,5R,7S,9S,10S,11 R,12S,13R)-7-({[1,1 -dimethyl-2-({[4(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl]carbamoyl}oxy)-2-(2{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2yQoxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methaxyimino)-6· methyltetrahydro-2H-pyran-2-yl]oxy}-315l7,9l11,13-hexamethyl-6,14-dioxo-12{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3methylbutanoate;
• (2R.3S.4R.5R.7S.9S. 1OS, 11 R, 12S, 13R)-7-[({1.1 -dimethyl-2[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3Rt4R,5R16R)-5hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)10-({(2S,3R,6R)-3-hydroxy-6-methyl-4-[(2,2,2-trifluoroethoxy)imino]tetrahydro2H-pyran-2-yl}oxy )-3.5.7,9,11,13-hexamethyl-6,14-dioxo-12-{((2S,7R)-2,4,5trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
• (2R,3S,4R,5R,7S,9S110S,11 R, 12S,13R)-7-[({ 1,1 -dimethyl-2[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-10-{[(2S,3R,6R)-4-(ethoxyimino)3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-2-(2-{[(2R,3R,4R,5R16R)-5hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-
3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1,4oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate.
8. Process for preparing a compound of formula (I) according to Claim 1, in which Y represents a group -(C=O)-NR2R3. characterized in that: a compound of formula (IB):
o in which Rt and Z are as defined for the compounds of formula (I) in Claim 1, is reacted with a compound of formula (II) HNR2R3 in which R2 and R3 are as defined
I4l for the compounds of formula (I) in Claim 1, in the presence of a carbonyl dérivative and a base.
9. Process for preparing a compound of formula (I) according to Claim 1, tn which Y
5 represents a group -(C=O)-NR2R3, characterized in that:
b-1) a compound of formula (V):
O in which Ri, R2 and R3 are as defined for a compound of formula (I) in Claim 1, is
10 reacted with an oxidizing agent to obtain a compound of formula (VI):
b-2) the compound of formula (VI) thus obtained is reacted with a compound of formula (VII):
15 ZNH2(V1I) in which Z is as defined for compound (I) in Claim 1, in the presence of a reducing agent.
«
142
10. Process for preparing a compound of formula (I) according to Claim 1, in which Y represents a hydrogen atom, characterized in that:
c-1) a compound of formula (VIII):
5 in which Rt is as defined for compound (I) in Claim 1, is reacted with an oxidizing agent to obtain a compound of formula (IX):
O c-2) the compound of formula (IX) thus obtained is reacted with a compound of 10 formula (VII):
ZNH2 (VII) in which Z is as defined for compound (I) in Claim 1, in the presence of a reducing agent.
11. Process for preparing a compound of formula (I) according to Claim 1, In which Y represents a group -(C=O)-O-Rt8, characterized in that:
143 a compound of formula (XXI):
in which Z and Ri are as defined for a compound of formula (I) in Claim 1, is reacted with an alcohol of formula HO-Rie (XXII) în which Rie is as defined for a 5 compound of formula (I) in Claim 1, in the presence of a base.
în which:
10 - Ri, R2 and R3 are as defined for the compounds of formula (I) in Claim 1.
.1
144 in which:
- Ri is as defined for the compounds of formula (I) in Claim 1.
14. Médicament, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 7, in the form of a base or of an acid-addition sait.
15. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 7, in the form of a base or of an acid-addition sait, and also at least one pharmaceutically acceptable excipient.
16. Compound according to any one of Claims 1 to 7, for its use for the prévention and/or treatment of bacterial infections caused by gram-positive microorganisms and mycobacteria.
17. Compound according to any one of Claims 1 to 7, for its use for the prévention and/or treatment of infectious diseases chosen from tuberculosis, leprosy, nocardiosis, diphtheria, pulmonary mycobacteria! infection, cutaneous mycobacteria! infection, atypic mycobacteria! infection and mycobacteriosis.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1258744 | 2012-09-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA17212A true OA17212A (en) | 2016-04-05 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI669302B (en) | 5-methyl-1,3,4-oxadiazol-2-yl compounds | |
| JP7184646B2 (en) | Biaryl monobactam compounds and methods of their use for treating bacterial infections | |
| EP2061762B1 (en) | Pyrazine compounds, their use and methods of preparation | |
| JP5143000B2 (en) | 8-methoxy-9H-isothiazolo [5,4-b] quinoline-3,4-dione and related compounds as anti-infective agents | |
| US11834436B2 (en) | Tetrazole containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof | |
| US20210040066A1 (en) | Tetrahydroisoquinoline compound, preparation method therefor, pharmaceutical composition containing same, and use thereof | |
| KR20200013718A (en) | Heteroaromatic Compounds as Banin Inhibitors | |
| DK2897970T3 (en) | MACROLIDE DERIVATIVES, PREPARING thereof, AND THERAPEUTIC APPLICATION | |
| ES2576082T3 (en) | Paroxetine derivative | |
| OA17212A (en) | Macrolide derivatives, preparation thereof and therapeutic use thereof. | |
| CN106167486B (en) | Monocycle class gyrase and topoisomerase I V inhibitor | |
| JP2008519842A (en) | 8A, 9-dihydro-4A-H-isothiazolo [5,4-B] quinoline-3,4-dione and related compounds as anti-infective agents | |
| JP2008519842A5 (en) | ||
| RU2782469C2 (en) | Apoptosis-inducing agents | |
| WO2014195705A1 (en) | Novel pyrrole derivatives | |
| CA2914262A1 (en) | Novel pyrrole derivatives | |
| WO2022159491A1 (en) | Rifamycin analogs | |
| EP1845096A1 (en) | 12-Aza-epothilones, process for their preparation and their use as antiproliferative agents | |
| EA045146B1 (en) | HETEROAROMATIC COMPOUNDS AS VANINE INHIBITORS | |
| WO2014195718A1 (en) | 3,4-dihydroxy-pyrrole derivatives as antibacterial agents | |
| WO2014195700A1 (en) | Novel pyrrole derivatives | |
| WO2014195697A1 (en) | Novel pyrrole derivative |