ZA200301540B - Nucleoside derivatives for the treatment of Hepatitis C. - Google Patents
Nucleoside derivatives for the treatment of Hepatitis C. Download PDFInfo
- Publication number
- ZA200301540B ZA200301540B ZA200301540A ZA200301540A ZA200301540B ZA 200301540 B ZA200301540 B ZA 200301540B ZA 200301540 A ZA200301540 A ZA 200301540A ZA 200301540 A ZA200301540 A ZA 200301540A ZA 200301540 B ZA200301540 B ZA 200301540B
- Authority
- ZA
- South Africa
- Prior art keywords
- ribofuranosyl
- purine
- hydrogen
- alkyl
- adenosine
- Prior art date
Links
- 150000003833 nucleoside derivatives Chemical class 0.000 title description 5
- 208000005176 Hepatitis C Diseases 0.000 title 1
- -1 NR'RS Chemical class 0.000 claims description 450
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 334
- 125000000217 alkyl group Chemical group 0.000 claims description 132
- 229910052739 hydrogen Inorganic materials 0.000 claims description 132
- 239000001257 hydrogen Substances 0.000 claims description 132
- 150000001875 compounds Chemical class 0.000 claims description 109
- 125000003118 aryl group Chemical group 0.000 claims description 81
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 73
- 125000000623 heterocyclic group Chemical group 0.000 claims description 72
- 229910052736 halogen Inorganic materials 0.000 claims description 69
- 150000002367 halogens Chemical class 0.000 claims description 69
- 125000003545 alkoxy group Chemical group 0.000 claims description 64
- 239000000203 mixture Substances 0.000 claims description 55
- 239000000126 substance Substances 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 48
- 229910052757 nitrogen Inorganic materials 0.000 claims description 47
- 241000711549 Hepacivirus C Species 0.000 claims description 45
- 125000004432 carbon atom Chemical group C* 0.000 claims description 45
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 40
- 125000001424 substituent group Chemical group 0.000 claims description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 35
- 229910052801 chlorine Inorganic materials 0.000 claims description 33
- 239000000460 chlorine Substances 0.000 claims description 33
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 32
- 125000004414 alkyl thio group Chemical group 0.000 claims description 30
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- 229910052731 fluorine Inorganic materials 0.000 claims description 26
- 239000011737 fluorine Substances 0.000 claims description 26
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 26
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 25
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 25
- 125000004104 aryloxy group Chemical group 0.000 claims description 25
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 25
- 229910052794 bromium Inorganic materials 0.000 claims description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 125000005110 aryl thio group Chemical group 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 18
- 125000004946 alkenylalkyl group Chemical group 0.000 claims description 17
- 125000005038 alkynylalkyl group Chemical group 0.000 claims description 16
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 14
- 239000011630 iodine Substances 0.000 claims description 14
- 229910052740 iodine Inorganic materials 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 230000001404 mediated effect Effects 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 208000015181 infectious disease Diseases 0.000 claims description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 claims description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims 82
- 150000002431 hydrogen Chemical class 0.000 claims 77
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims 43
- 229960005305 adenosine Drugs 0.000 claims 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 28
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 23
- 150000002148 esters Chemical class 0.000 claims 22
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims 20
- 150000003839 salts Chemical class 0.000 claims 20
- 150000002170 ethers Chemical class 0.000 claims 8
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 7
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims 5
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 5
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims 4
- KLSXCABJCOPHLP-IVZWLZJFSA-N 5-ethyl-1-[(2r,4s,5r)-5-(hydroxymethyl)-4-methoxyoxolan-2-yl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(CC)=CN1[C@@H]1O[C@H](CO)[C@@H](OC)C1 KLSXCABJCOPHLP-IVZWLZJFSA-N 0.000 claims 3
- 241001465754 Metazoa Species 0.000 claims 3
- 229940035893 uracil Drugs 0.000 claims 3
- MRRXXEGKMDBWFH-QYVSTXNMSA-N (2r,3r,4s,5r)-2-(6-amino-8-morpholin-4-ylpurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1COCCN1C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O MRRXXEGKMDBWFH-QYVSTXNMSA-N 0.000 claims 2
- OFSXZWPYWPGZEB-LSCFUAHRSA-N (2r,3r,4s,5r)-2-[6-amino-8-(2-phenylethylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=CC=CC=1CCNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OFSXZWPYWPGZEB-LSCFUAHRSA-N 0.000 claims 2
- FECURFWCESRSEY-WOUKDFQISA-N (2r,3r,4s,5r)-2-[6-amino-8-(prop-2-enylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=CCNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O FECURFWCESRSEY-WOUKDFQISA-N 0.000 claims 2
- MFSVWWMNPRVKLJ-WOUKDFQISA-N (2r,3r,4s,5r)-2-[6-amino-8-(prop-2-ynylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C#CCNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O MFSVWWMNPRVKLJ-WOUKDFQISA-N 0.000 claims 2
- WIVKXJACYNVLOA-XNIJJKJLSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-fluorophenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(F)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O WIVKXJACYNVLOA-XNIJJKJLSA-N 0.000 claims 2
- AFTWSDWFGCVHHB-DPHITLOKSA-N (2r,3r,4s,5r)-2-[6-amino-8-[[(2r)-1-phenylpropan-2-yl]amino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C([C@@H](C)NC=1N(C2=NC=NC(N)=C2N=1)[C@H]1[C@@H]([C@H](O)[C@@H](CO)O1)O)C1=CC=CC=C1 AFTWSDWFGCVHHB-DPHITLOKSA-N 0.000 claims 2
- OCMSLPSATJLTEP-SCFUHWHPSA-N (2r,3r,4s,5r)-2-[6-amino-8-[methyl(2-phenylethyl)amino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound N=1C2=C(N)N=CN=C2N([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)C=1N(C)CCC1=CC=CC=C1 OCMSLPSATJLTEP-SCFUHWHPSA-N 0.000 claims 2
- HMHOCXPPRRVMLR-RRFJBIMHSA-N (2r,3s,5r)-5-[6-amino-8-(3-phenylpropylamino)purin-9-yl]-2-(hydroxymethyl)oxolan-3-ol Chemical compound C=1C=CC=CC=1CCCNC1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 HMHOCXPPRRVMLR-RRFJBIMHSA-N 0.000 claims 2
- PPSNVMAMKMAPBC-ARFHVFGLSA-N (2r,3s,5r)-5-[6-amino-8-(4-phenylbutylamino)purin-9-yl]-2-(hydroxymethyl)oxolan-3-ol Chemical compound C=1C=CC=CC=1CCCCNC1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PPSNVMAMKMAPBC-ARFHVFGLSA-N 0.000 claims 2
- MYZAQMXBOMNLHQ-YNEHKIRRSA-N (2r,3s,5r)-5-[6-amino-8-(benzylamino)purin-9-yl]-2-(hydroxymethyl)oxolan-3-ol Chemical compound C=1C=CC=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 MYZAQMXBOMNLHQ-YNEHKIRRSA-N 0.000 claims 2
- ZPTGKOCHKARWPA-UHFFFAOYSA-N 4-amino-1-[2,2-difluoro-3-hydroxy-4-(hydroxymethyl)cyclopentyl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1C1C(F)(F)C(O)C(CO)C1 ZPTGKOCHKARWPA-UHFFFAOYSA-N 0.000 claims 2
- ZAYHVCMSTBRABG-UHFFFAOYSA-N 5-Methylcytidine Natural products O=C1N=C(N)C(C)=CN1C1C(O)C(O)C(CO)O1 ZAYHVCMSTBRABG-UHFFFAOYSA-N 0.000 claims 2
- ZAYHVCMSTBRABG-JXOAFFINSA-N 5-methylcytidine Chemical compound O=C1N=C(N)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 ZAYHVCMSTBRABG-JXOAFFINSA-N 0.000 claims 2
- SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 2
- VYSCKHGOLQAMAT-KQYNXXCUSA-N adenosine 1-oxide Chemical compound C12=NC=N(=O)C(N)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VYSCKHGOLQAMAT-KQYNXXCUSA-N 0.000 claims 2
- 125000006309 butyl amino group Chemical group 0.000 claims 2
- 229940104302 cytosine Drugs 0.000 claims 2
- 229960002949 fluorouracil Drugs 0.000 claims 2
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 2
- BIXYYZIIJIXVFW-UUOKFMHZSA-N (2R,3R,4S,5R)-2-(6-amino-2-chloro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O BIXYYZIIJIXVFW-UUOKFMHZSA-N 0.000 claims 1
- TXWHPSZYRUHEGT-UUOKFMHZSA-N (2r,3r,4s,5r)-2-(2-amino-6-chloropurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C12=NC(N)=NC(Cl)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O TXWHPSZYRUHEGT-UUOKFMHZSA-N 0.000 claims 1
- PWXGIJDIDZCGDO-XNIJJKJLSA-N (2r,3r,4s,5r)-2-(6-amino-8-benzylsulfanylpurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=CC=CC=1CSC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O PWXGIJDIDZCGDO-XNIJJKJLSA-N 0.000 claims 1
- FDBPSTSSWWLZRH-IOSLPCCCSA-N (2r,3r,4s,5r)-2-(6-amino-8-ethoxypurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound CCOC1=NC2=C(N)N=CN=C2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O FDBPSTSSWWLZRH-IOSLPCCCSA-N 0.000 claims 1
- YCXGCAXXPRSCHN-XNIJJKJLSA-N (2r,3r,4s,5r)-2-(6-amino-8-phenylmethoxypurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=CC=CC=1COC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YCXGCAXXPRSCHN-XNIJJKJLSA-N 0.000 claims 1
- CNYYZAAPULRJDG-IDTAVKCVSA-N (2r,3r,4s,5r)-2-(6-amino-8-piperidin-1-ylpurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1CCCCN1C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O CNYYZAAPULRJDG-IDTAVKCVSA-N 0.000 claims 1
- JCLULUZARUKLJB-IOSLPCCCSA-N (2r,3r,4s,5r)-2-[6-amino-8-(2-hydroxyethylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound OCCNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O JCLULUZARUKLJB-IOSLPCCCSA-N 0.000 claims 1
- HZNJYOOMCOVLRK-SDBHATRESA-N (2r,3r,4s,5r)-2-[6-amino-8-(2-thiophen-2-ylethylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=CSC=1CCNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O HZNJYOOMCOVLRK-SDBHATRESA-N 0.000 claims 1
- JQQLDLNDWRBISW-SCFUHWHPSA-N (2r,3r,4s,5r)-2-[6-amino-8-(3,4-dihydro-1h-isoquinolin-2-yl)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1CC2=CC=CC=C2CN1C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O JQQLDLNDWRBISW-SCFUHWHPSA-N 0.000 claims 1
- ASLRZHBTVUIPEG-SCFUHWHPSA-N (2r,3r,4s,5r)-2-[6-amino-8-(3-phenylpropylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=CC=CC=1CCCNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O ASLRZHBTVUIPEG-SCFUHWHPSA-N 0.000 claims 1
- XQNAYEAVGGDDAM-NVQRDWNXSA-N (2r,3r,4s,5r)-2-[6-amino-8-(4-phenylbutylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=CC=CC=1CCCCNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O XQNAYEAVGGDDAM-NVQRDWNXSA-N 0.000 claims 1
- VPBBBXAWDHCHSQ-NVQRDWNXSA-N (2r,3r,4s,5r)-2-[6-amino-8-(4-phenylpiperazin-1-yl)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1CN(C=2C=CC=CC=2)CCN1C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VPBBBXAWDHCHSQ-NVQRDWNXSA-N 0.000 claims 1
- XBPUFDODTYBKPH-XNIJJKJLSA-N (2r,3r,4s,5r)-2-[6-amino-8-(benzylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=CC=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O XBPUFDODTYBKPH-XNIJJKJLSA-N 0.000 claims 1
- FHXATHZJDXWJNU-IOSLPCCCSA-N (2r,3r,4s,5r)-2-[6-amino-8-(ethylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound CCNC1=NC2=C(N)N=CN=C2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O FHXATHZJDXWJNU-IOSLPCCCSA-N 0.000 claims 1
- NHKHDHFPJYVHCW-WVSUBDOOSA-N (2r,3r,4s,5r)-2-[6-amino-8-(naphthalen-1-ylmethylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=CC2=CC=CC=C2C=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NHKHDHFPJYVHCW-WVSUBDOOSA-N 0.000 claims 1
- UYOQKCQQFRJMSL-WOUKDFQISA-N (2r,3r,4s,5r)-2-[6-amino-8-(propan-2-ylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound CC(C)NC1=NC2=C(N)N=CN=C2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O UYOQKCQQFRJMSL-WOUKDFQISA-N 0.000 claims 1
- SMOCJUBPHMQTDW-SDBHATRESA-N (2r,3r,4s,5r)-2-[6-amino-8-(pyridin-3-ylmethylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=CN=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O SMOCJUBPHMQTDW-SDBHATRESA-N 0.000 claims 1
- QQMFHKFZEYPMON-SCFUHWHPSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(2,5-dimethoxyphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound COC1=CC=C(OC)C(CNC=2N(C3=NC=NC(N)=C3N=2)[C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 QQMFHKFZEYPMON-SCFUHWHPSA-N 0.000 claims 1
- YLHDPTTWGXGFIT-NVQRDWNXSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-tert-butylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=CC(C(C)(C)C)=CC=C1CNC1=NC2=C(N)N=CN=C2N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 YLHDPTTWGXGFIT-NVQRDWNXSA-N 0.000 claims 1
- IJUBGXVQZIKNJI-XNIJJKJLSA-N (2r,3r,4s,5r)-2-[6-amino-8-[2-(1-methylpyrrol-2-yl)ethylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound CN1C=CC=C1CCNC1=NC2=C(N)N=CN=C2N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IJUBGXVQZIKNJI-XNIJJKJLSA-N 0.000 claims 1
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- SITPPNUSTDASFP-LSCFUAHRSA-N (2r,3r,4s,5r)-2-[6-amino-8-[2-(4-hydroxyphenyl)ethylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(O)C=CC=1CCNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O SITPPNUSTDASFP-LSCFUAHRSA-N 0.000 claims 1
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- 125000000165 tricyclic carbocycle group Chemical group 0.000 description 1
- 125000002264 triphosphate group Chemical class [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229940100050 virazole Drugs 0.000 description 1
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Description
. NUCLEOSIDE DERIVATIVES FOR THE TREATMENT OF HEPATITIS C
The invention relates to nucleoside derivatives as inhibitors of HCV Replicon
RNA replication. In particular, the invention is concerned with novel and known purine and pyrimidine nucleoside derivatives, their use as inhibitors of subgenomic Hepatitis C Virus (HCV) RNA replication and pharmaceutical compositions of such compounds. For the novel purine and pyrimidine nucleoside derivatives the invention is also concerned with a process for their manufacture, pharmaceutical compositions and the use of such compounds in medicine. The compounds of this invention have potential use as therapeutic agents for the treatment of HCV infections.
Hepatitis C virus is the leading cause of chronic liver disease throughout the world. Patients infected with HCV are at risk of developing cirrhosis of the liver and subsequent hepatocellular carcinoma and hence HCV is the major indication for liver transplantation. Only two approved therapies are currently available for the treatment of HCV infection (R.G. Gish, Sem.Liver.Dis., 1999, 19, 35). These are interferon-oe monotherapy and, more recently, combination therapy of the nucleoside analogue, ribavirin (Virazole), with interferon-o.
Ribavirin is a broad spectrum antiviral agent with activity against a range of
DNA and RNA viruses (R.A.Smith and W. Kirkpatrick (Eds.): Ribavirin — A Broad
Spectrum Antiviral Agent, Academic Press, New York, 1980) but its mechanism of action has not been conclusively established and a number of distinct properties of ribavirin have been identified which may vary in relative importance for differing viral disease conditions. These properties include mediation of the immune response (C. D. Hultgren et al, ].Gen.Virol., 1998, 79, 2381), lowering of serum alanine aminotransferase (ALT) levels (G. Dusheiko et al, J. Hepatol.,1996, 25, . 591), inhibition as the monophosphate of inosine monophosphate dehydrogenase
(IMPDH) (D.G.Streeter et al, Proc.Natl.Acad.Sci., 1973, 70,1174) and direct inhibition of viral DNA or RNA replication (R.W.Sidwell et al, Science, 177,705).
Many of the drugs approved for the treatment of viral infections are ] nucleosides or nucleoside analogues and most of these nucleoside analogue drugs inhibit viral replication, following conversion to the corresponding triphosphates, through inhibition of the viral polymerase enzymes. This conversion to the triphosphate is commonly mediated by cellular kinases and therefore the direct evaluation of nucleosides as inhibitors of HCV replication is only conveniently carried out using a cell-based assay. For HCV the availability of a true cell-based viral replication assay or animal model of infection is lacking.
Hepatitis C virus belongs to the family of Flaviridae. It is an RNA virus, the
RNA genome encoding a large polyprotein which after processing produces the necessary replication machinery to ensure synthesis of progeny RNA. It is believed that most of the non-structural proteins encoded by the HCV RNA genome are involved in RNA replication. Lohmann et al. [V. Lohmann et al., Science, 1999, 285, 110-113] have described the construction of a Human Hepatoma (Huh7) cell line in which subgenomic HCV RNA molecules have been introduced and shown to replicate with high efficiency. It is believed that the mechanism of RNA replication in these cell lines is identical to the replication of the full length HCV
RNA genome in infected hepatocytes. The subgenomic HCV cDNA clones used for the isolation of these cell lines have formed the basis for the development of a cell- based assay for identifying nucleoside analogue inhibitors of HCV replication.
The compounds of formula I have been shown to be inhibitors of subgenomic Hepatitis C Virus replication in a hepatoma cell line. These compounds have the potential to be efficacious as antiviral drugs for the treatment of HCV infections in human.
This object can be achieved by use of compounds of formula I
HO
, Ye
I : . y X $ =
R'R wherein
R' is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxy, halogen, cyano, isocyano or azido;
R? is hydrogen, hydroxy, alkoxy, chlorine, bromine or iodine; ’ R’ is hydrogen; or
R? and R? together represent =CHa; or
R? and R® represent fluorine;
Xis O, Sor CH; a, b, ¢, d denoting asymmetric carbon atoms each of which is substituted with 4 different substituents; and
B signifies a purine base B1 which is connected through the 9-nitrogen of formula
IN
N
NT TN ge [ae >—R° BH rR? N N wherein
R* is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl,
NR’R®, halogen or SH;
R’ is hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, heterocyclyl, heterocyclylamino, halogen, NR’R®, NHOR®, NHNR'R® or
SH;
RS is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl,
NR’R?, halogen, SH or cyano;
R’ and R® are independently of each other hydrogen, alkyl, aryl, hydroxyalkyl, alkenylalkyl, alkynylalkyl, cycloalkyl or acyl;
R? is hydrogen, alkyl or aryl; or
B signifies an oxidised purine base B2 which is connected through the 9-nitrogen of formula
R®
O_ N° od N\ 6 : 1
PN [| Dr e2
R* N N wherein
R* R’ and R® are as defined above; or
B signifies a purine base B3 which is connected through the 9-nitrogen of formula
Y
10
R ~N N 1 N 6
PN | : >—R® B3 4 N
R wherein
R* and R® are as defined above;
R" is hydrogen, alkyl or aryl;
Y is O,S or NR!
R" is hydrogen, hydroxy, alkyl, OR’, heterocyclyl or NR'R%;
R’, R® and R® are as defined above; or
B signifies a pyrimidine base B4 which is connected through the 1-nitrogen of formula
R'2 13
NZ R
A | Ba ‘ N ‘ 15 wherein
ZisOorsS;
R'? is hydrogen, hydroxy, alkyl, alkoxy, haloalkyl, alkylthio, aryl, aryloxy, arylthio, heterocyclyl, heterocyclylamino, halogen, NR’R?, NHOR?, NHNR’R® or SH;
R" is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl or halogen; ) R’, R® and R’ are as defined above; or
B signifies a pyrimidine base B5 which is connected through the 1-nitrogen of formula
Y rR R* ™N
A | Bs
N wherein
Y,Z,R" and R"” are as defined above for the treatment of diseases mediated by the Hepatitis C Virus (HIV) or for the preparation of a medicament for such treatment.
The term “alkyl” as used herein denotes an unsubstituted or substituted straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl including their isomers. Preferably, the term “alkyl” denotes an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms.
Suitable substituents for the alkyl chain can be selected from one or more of aryl, heterocyclyl, cycloalkyl, ) nitro, cyano, azido, amino, alkyl amino, dialkyl amino, cycloalkyl amino, aryl amino, diarylamino, } heterocyclyl amino, hydroxy, alkoxy, aryloxy, heterocyclyloxy, cycloalkoxy, thio, alkylthio, arylthio, heterocyclylthio,
alkyl carbonyl, cycloalkyl carbonyl, aryl carbonyl, heterocyclyl carbonyl, ] carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, heterocyclylaminocarbonyl.
Aryl, heterocyclyl or cycloalkyl as substituents for the alkyl group can also be substituted with one or more methyl, ethyl, n-propyl, i-propyl, tert.-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propyloxy, amino, alkylamino, arylamino, dialkylamino, diarylamino, heterocyclylamino,vinyl, allyl, carboxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, diarylaminocarbonyl, heterocyclylaminocarbonyl, fluorine, chlorine, bromine, iodine, cyano or nitro.
Alkyl in R' is preferably an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms and most preferred methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl or pentyl.
Alkyl in R* is preferably an unsubstituted or substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms. Suitable substituents for the alkyl group are selected from one or more of aryl or heterocyclyl as defined below. The aryl or heterocyclyl can also be alkylated with one or more methyl or ethyl or halogenated with fluorine, chlorine, bromine or iodine. Preferably alkyl in
R* is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, phenylmethyl (benzyl), chlorphenylmethyl, phenylethyl, phenylpropyl, pyridylmethyl, chlorpyridylmethyl, pyridylethyl, pyridylpropyl, thienylmethyl, thienylethyl, thienylpropyl.
Alkyl in R is preferably an unsubstituted or substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms. Suitable substituents for the alkyl group are selected from one or more of aryl or heterocyclyl as defined below. The aryl or heterocyclyl can also be alkylated with one or more methyl or ethyl or halogenated with fluorine, chlorine, bromine or iodine. Preferably alkyl in . R’ is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, phenylmethyl (benzyl), chlorphenylmethyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, : 30 pyridylmethyl, chlorpyridylmethyl, pyridylethyl, pyridylpropyl, thienylmethyl, thienylethyl, thienylpropyl.
Alkyl in R® is preferably an unsubstituted or substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms. Suitable substituents for the alkyl group are selected from one or more of hydroxy, aryl or heterocyclyl as defined below. The aryl or heterocyclyl can also be alkylated with one or more - methyl or ethyl or halogenated with fluorine, chlorine, bromine or iodine.
Preferably alkyl in R® is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.- butyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 1-hydroxy- 1-methyl-ethyl, 2-hydroxy-2-methyl-ethyl, phenylmethyl (benzyl), chlorphenylmethyl, phenylethyl, phenylpropyl, pyridylmethyl, chlorpyridylmethyl, pyridylethyl, pyridylpropyl, thienylmethyl, thienylethyl, thienylpropyl.
Alkyl in R” and R® (for NR’R®) is independently of each other preferably an unsubstituted or substituted straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms. Suitable substituents for the alkyl group are selected from one or more of aryl, heterocyclyl, cycloalkyl, nitro, amino, alkyl amino, dialkyl amino, cycloalkyl amino, aryl amino, heterocyclyl amino, alkyl carbonyl, cycloalkyl carbonyl, aryl carbonyl, heterocyclyl carbonyl. The aryl, heterocyclyl or cycloalkyl can also be substituted with one or more methyl, ethyl, n-propyl, i-propyl, tert.-butyl, trifluoromethyl, methoxy, ethoxy, propyloxy, amino, vinyl, allyl, carboxy, alkylcarbonyl, fluorine, chlorine, bromine, iodine or aminosulphonyl. Preferably alkyl in R’ and R® is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, aminomethyl, aminoethyl}, aminopropyl, aminobutyl, aminopentyl, chlormethyl, chlorethyl, chlorpropyl, cyanomethyl, cyanoethyl, cyanopropyl, phenylmethyl (benzyl), 1-phenylethyl, 2- phenylethyl, 1(S)-methyl-2-phenylethyl, 1(R)-methyl-2-phenylethyl, 1- phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, 1-benzyl-1-methylethyl, chlorphenylmethyl, dichlorphenylmethyl, 2- chlorphenylethyl, 3-chlorphenylethyl, 4-chlorphenylethyl, dichlorphenylethyl, tolylmethyl, tolylethyl, tolylpropyl, tolylbutyl, methoxyphenylmethyl, methoxyphenylethyl, methoxyphenylpropyl, methoxyphenylbutyl, aminophenylmethyl, aminophenylethyl, aminophenylpropyl, aminophenylbutyl, phenolmethyl, phenolethyl, phenolpropyl, phenolbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, 2-pyridylmethyl, 3-pyridylmethyl, , 4-pyridylmethyl, pyridylethyl, pyridylpropyl, methylpyridylmethyl, methylpyridylethyl, methylpyridylpropyl, chlorpyridylmethyl, chlorpyridylethyl, , chlorpyridylpropyl, pyrrolylmethyl, pyrrolylethyl, pyrrolylpropyl, pyrrolylbutyl, methylpyrrolylmethyl, methylpyrrolylethyl, methylpyrrolylpropyl, methylpyrrolylbutyl, imidazolylmethyl, imidazolylethyl, imidazolylpropyl, imidazolylbutyl, 2-(3-indolyl)methyl, 2-(3-indolyl)ethyl, 2-(3-indolyl)propyl,
morpholinylmethyl, morpholinylethyl, morpholinylpropyl, morpholinylbutyl, thienylmethyl, thienylethyl, 2-(2-thienyl)ethyl, thienylpropyl, thienylbutyl, . cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, 2-(4-cyanomethylphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2- : 5 (4-hydroxyphenyl)ethyl, (5-chloro-2-methoxyphenyl) methyl, (2- methylphenyl)methyl, (3-methyl)butyl, 4-(aminophenyl)methyl, 2-(4- morpholinyl)ethyl, 2(R,S)-phenylpropyl, 2-(4-Methylphenyl)ethyl, 2-(1-methyl-2- pyrrolyl)ethyl, 2-(4-aminosulphonylphenyl)ethyl, 2-ethyl-4-imidazolyl, methyl-1- naphthyl, 2-(4-chlorophenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl, 4-fluorobenzyl, 4- (hydroxycarbonyl)benzyl, 4-trifluoromethyl)benzyl, 2,5-dimethoxy)benzyl, 2-(2- thienyl)ethyl, 2-(4-aminophenyl)ethyl, 2-Phenoxyethyl, (2-thienyl)methyl, 4-(tert-
Butyl)benzyl, 1(R)-Phenylethyl, 1(S)-Phenylethyl, 2-Hydroxy-1(S)-phenyl)ethyl.
Alkyl in R’ (for NHOR’) is preferably an unsubstituted or substituted straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl including their isomers. A suitable substituent for the alkyl group is the aryl group as defined below. The aryl can also be substituted with one or more methyl, ethyl, trifluoromethyl, methoxy, ethoxy, hydroxy, amino, fluorine, chlorine, bromine or iodine. Preferred alkyl in R’ is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, chlorphenylmethyl, chlorphenylethyl, tolylmethyl, tolylethyl, tolylpropyl, methoxyphenylmethyl, methoxyphenylethyl, aminophenylmethyl, aminophenylethyl, phenolmethyl, phenolethyl.
Alkyl in R" is preferably an unsubstituted or substituted straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl including their isomers. A suitable substituent for the alkyl group is the aryl group as defined below. The aryl can also be substituted with one or more methyl, ethyl, trifluoromethyl, methoxy, ethoxy, hydroxy, amino, fluorine, chlorine, bromine, iodine. Preferred alkyl in R'® is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, chlorphenylmethyl, chlorphenylethyl, tolylmethyl, tolylethyl, tolylpropyl, methoxyphenylmethyl, methoxyphenylethyl, aminophenylmethyl, aminophenylethyl, phenolmethyl, phenolethyl.
Alkyl in R"! is preferably an unsubstituted or substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms. A suitable substituent : for the alkyl group is the aryl group as defined below. The aryl can also be substituted with one or more methyl, ethyl, trifftuoromethyl, methoxy, ethoxy, : 5 hydroxy, amino, fluorine, chlorine, bromine, iodine. Most preferred alkyl in Ris methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, chlorphenylmethyl, chlorphenylethyl, tolylmethyl, tolylethyl, tolylpropyl, methoxyphenylmethyl, methoxyphenylethyl, aminophenylmethyl, aminophenylethyl, phenolmethyl, phenolethyl.
Alkyl in R'? is preferably an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms and most preferred methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl or pentyl.
Alkyl in R" is preferably an unsubstituted or substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl or pentyl, hexyl or heptyl. Suitable substituents for the alkyl group are selected from one or more of aryl, heterocyclyl, alkoxy or amino. The aryl or heterocyclyl can also be substituted with one or more methyl, trifluoromethyl, methoxy or amino. Preferably alkyl in R" is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, methoxymethyl, ethoxymethyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, phenylmethyl (benzyl), phenylethyl, tolylmethyl, tolylethyl, methoxyphenylmethyl, methoxyphenylethyl, aminophenylmethyl, aminophenylethyl, phenolmethyl, phenolethyl, pyridylmethyl, pyridylethyl, methylpyridylmethyl, pyrrolylmethyl, pyrrolylethyl, methylpyrrolylmethyl, methylpyrrolylethyl, imidazolylmethyl, imidazolylethyl, thienylmethyl, thienylethyl.
The term “cycloalkyl” as used herein denotes an optionally substituted cycloalkyl group containing 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, which can also be fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or : tricyclic heterocycle or carbocycle, e.g. to phenyl.
Suitable substituents for cycloalkyl can be selected from one or more of those named for alkyl.
Cycloalkyl in R’ is preferably an optionally substituted cycloalkyl group containing 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, i cyclohexyl or cycloheptyl. Suitable substituents for the cycloalkyl group are selected from aryl, heterocyclyl, cycloalkyl, hydroxy, nitro, halogen, amino, alkyl amino, . 5 dialkyl amino, cycloalkyl amino, aryl amino, heterocyclyl amino. The aryl or heterocyclyl can also be substituted with one or more of methyl, ethyl, trifluoromethyl, methoxy, amino, hydroxy, carboxy, fluorine, chlorine, bromine or iodine. Preferably cycloalkyl in R® is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclohexyl substituted with one or more aryl, heterocyclyl, methyl, amino, hydroxy, fluorine or chlorine.
Cycloalkyl in R” and R® (for NR’R®) is independently of each other preferably an optionally substituted cycloalkyl group containing 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Suitable substituents for the cycloalkyl group are selected from aryl, heterocyclyl, cycloalkyl, hydroxy, nitro, halogen, amino, alkyl amino, dialkyl amino, cycloalkyl amino, aryl amino, heterocyclyl amino. The aryl or heterocyclyl can also be substituted with one or more of methyl, ethyl, trifluoromethyl, methoxy, amino, hydroxy, carboxy, fluorine, chlorine, bromine or iodine. Preferably cycloalkyl in R” and R® is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclohexyl substituted with one or more aryl, heterocyclyl, methyl, amino, hydroxy, fluorine or chlorine.
Cycloalkyl in R" is preferably an optionally substituted cycloalkyl group containing 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Suitable substituents for the cycloalkyl group are selected from one or more of aryl, heterocyclyl, cycloalkyl, hydroxy, nitro, halogen, amino, alkyl amino, dialkyl amino, cycloalkyl amino, aryl amino or heterocyclyl amino.
The aryl or heterocyclyl can also be substituted with one or more of methyl, ethyl, trifluoromethyl, methoxy, amino, hydroxy, carboxy, fluorine, chlorine, bromine or iodine. Preferably cycloalkyl in R" is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclohexyl substituted with one or more of aryl, heterocyclyl, methyl, amino, hydroxy, fluorine or chlorine. . The term “alkoxy” as used herein denotes an optionally substituted straight or branched chain alkyl-oxy group wherein the "alkyl" portion is as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, tert.- butyloxy, pentyloxy, hexyloxy, heptyloxy including their isomers.
Suitable substituents for the alkoxy group are selected from aryl, hydroxy, halogen or amino.
Alkoxy in R! is preferably an optionally substituted straight or branched chain alkyl-oxy group such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n- butyloxy, i-butyloxy, tert.-butyloxy. Suitable substituents for the alkoxy group are selected from one ore more of aryl, halogen or amino. Preferably alkoxy in R' is methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, tert.-butyloxy, phenylmethoxy, tolylmethoxy, fluormethoxy, chlormethoxy, bromomethoxy, fluorethoxy, chlorethoxy, bromomethoxy, aminomethoxy, aminoethoxy, aminopropyloxy.
Alkoxy in R? is preferably an optionally substituted straight or branched chain alkyl-oxy group such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n- butyloxy, i-butyloxy, tert.-butyloxy. Suitable substituents for the alkoxy group are selected from one ore more of aryl, halogen or amino. Preferably alkoxy in R* is methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, tert.-butyloxy, phenylmethoxy, tolylmethoxy, fluormethoxy, chlormethoxy, bromomethoxy, fluorethoxy, chlorethoxy, bromomethoxy, aminomethoxy, aminoethoxy, aminopropyloxy.
Alkoxy in R* is preferably an optionally substituted straight or branched chain alkyl-oxy group such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n- butyloxy, i-butyloxy, tert.-butyloxy. Suitable substituents for the alkoxy group are selected from one ore more of aryl, halogen or amino. Preferably alkoxy in R* is methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, tert.-butyloxy, phenylmethoxy, tolylmethoxy, fluormethoxy, chlormethoxy, bromomethoxy, fluorethoxy, chlorethoxy, bromomethoxy, aminomethoxy, aminoethoxy, aminopropyloxy.
Alkoxy in R’ is preferably an optionally substituted straight or branched chain alkyl-oxy group such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n- butyloxy, i-butyloxy, tert.-butyloxy. Suitable substituents for the alkoxy group are selected from one ore more of aryl, halogen or amino. Preferably alkoxy in R® is . methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, tert.-butyloxy, phenylmethoxy, tolylmethoxy, fluormethoxy, chlormethoxy, bromomethoxy, fluorethoxy, chlorethoxy, bromomethoxy, aminomethoxy, aminoethoxy, aminopropyloxy.
Alkoxy in R°® is preferably an optionally substituted straight or branched chain alkyl-oxy group such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n- - butyloxy, i-butyloxy, tert.-butyloxy. Suitable substituents for the alkoxy group are selected from one ore more of aryl, halogen or amino. Preferably alkoxy in R® is methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, tert.-butyloxy, phenylmethoxy, tolylmethoxy, fluormethoxy, chlormethoxy, bromomethoxy, fluorethoxy, chlorethoxy, bromomethoxy, aminomethoxy, aminoethoxy, aminopropyloxy.
Alkoxy in R'? is preferably an optionally substituted straight or branched chain alkyl-oxy group such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n- butyloxy, i-butyloxy, tert.-butyloxy. Suitable substituents for the alkoxy group are selected from one ore more of aryl, halogen or amino. Preferably alkoxy in RZ is methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, tert.-butyloxy, phenylmethoxy, tolylmethoxy, fluormethoxy, chiormethoxy, bromomethoxy, fluorethoxy, chlorethoxy, bromomethoxy, aminomethoxy, aminoethoxy, aminopropyloxy.
The term “alkoxyalkyl” as used herein denotes an alkoxy group as defined above which is bonded to an alkyl group as defined above. Examples are methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propyloxypropyl, methoxybutyl, ethoxybutyl, propyloxybutyl, butyloxybutyl, tert.-butyloxybutyl, methoxypentyl, ethoxypentyl, propyloxypentyl, butyloxypentyl, tert.-butyloxypentyl, pentyloxypentyl, methoxyhexyl, ethoxyhexyl, propyloxyhexyl, butyloxyhexyl, tert.-butyloxyhexyl, pentyloxyhexyl, hexyloxyhexyl, methoxyheptyl, ethoxyheptyl, propyloxyheptyl, butyloxyheptyl, tert.- butyloxyheptyl, pentyloxyheptyl, hexyloxyheptyl, heptyloxyheptyl including their isomers.
Alkoxyalkyl in R'? is preferably methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl.
The term “alkenyl” as used herein denotes to unsubstituted or substituted hydrocarbon chain radical having from 2 to 7 carbon atoms, preferably from 2 to 4 , carbon atoms, and having one or two olefinic double bonds, preferably one : olefinic double bond. Examples are vinyl, 1-propenyl, 2-propenyl (allyl) or 2- butenyl (crotyl).
The term “alkenylalkyl” as used herein denotes an alkenyl group as defined above which is bonded to an alkyl group as defined above. Examples are . vinylmethyl (e.g. 1-propenyl or 2-propenyl), 1-propenylmethyl, 2-propenylmethyl or 2-butenylmethyl.
Alkenylalkyl in R” and R® (for NR’R®) is independently of each other preferably 1-propenyl, 2-propenyl, 1-propenylmethyl or 2-propenylmethyl.
The term “alkynyl” as used herein denotes to unsubstituted or substituted hydrocarbon chain radical having from 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms, and having one or where possible two triple bonds, preferably one triple bond. Examples are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl.
The term “alkynylalkyl” as used herein denotes an alkynyl group as defined above which is bonded to an alkyl group as defined above. Examples are ethynylmethyl, 1-propynylmethyl, 2-propynylmethyl, 1-butynylmethyl, 2- butynylmethyl or 3-butynylmethyl.
Alkynylalkyl in R” and R® (for NR’R®) is independently of each other preferably ethynylmethyl, 1-propynylmethyl or 2-propynylmethyl.
The term “hydroxyalkyl” as used herein denotes a straight or branched chain alkyl group as defined above wherein 1, 2, 3 or more hydrogen atoms are substituted by a hydroxy group. Examples are hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxy-isobutyl, hydroxy-tert.-butyl, hydroxypentyl, hydroxyhexyl, hydroxyheptyl and the like.
Hydroxyalkylin R', R’, R®, R"? is preferably hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, hydroxy-isopropyl, hydroxybutyl, hydroxy- isobutyl, hydroxy-tert.-butyl, hydroxypentyl, hydroxyhexyl, hydroxyheptyl and preferred hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 1- propanol, 2-propanol, 1-butanol, 2-butanol. : The term “haloalkyl” as used herein denotes a straight or branched chain alkyl group as defined above wherein 1, 2, 3 or more hydrogen atoms are substituted by a halogen. Examples are 1-fluoromethyl, 1-chloromethyl, 1- bromomethyl, 1-iodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl,
triiodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2- fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3- i bromopropyl or 2,2,2-trifluoroethyl and the like.
Haloalkyl in R®, R'? and R" is preferably1-fluoromethyl, 1-chloromethyl, 1- bromomethyl, 1-iodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2- fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3- bromopropyl or 2,2,2-trifluoroethyl.
The term “alkylthio” as used herein denotes a straight or branched chain (alkyl)S- group wherein the "alkyl" portion is as defined above and can be therefore as well substituted with substituents selected from one or more aryl or heterocyclyl.
Examples are methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i- butyithio, tert.-butylthio, pentylthio, hexylthio, heptylthio, phenylmethylthio, phenylethylthio, phenylpropylthio, tolylmethylthio, tolylethylthio, tolylpropylthio, pyridylmethylthio, pyridylethylthio, pyridpropylthio, pyrrolylmethylthio, pyrrolylethylthio or pyrrolylpropylthio.
Alkylthio in R%, R>, R® and R"? is preferably methylthio, ethylthio, n- propylthio, i-propylthio, n-butylthio, i-butylthio, tert.-butylthio, pentylthio, hexylthio, heptylthio, phenylmethylthio, phenylethylthio, phenylpropylthio, phenylbutylthio, tolylmethylthio, tolylethylthio, tolylpropylthio, pyridylmethylthio, pyridylethylthio, pyridpropylthio, pyrrolylmethylthio, pyrrolylethylthio or pyrrolylpropylthio. Preferred alkylthio in R*, R®, R® and R" is methylthio, ethylthio, n-propylthio, i-propylthio, phenylmethylthio, phenylethylthio, phenylpropylthio, tolylmethylthio, tolylethylthio, pyridylmethylthio, pyridylethylthio, pyrrolylmethylthio or pyrrolylethylthio.
The term “aryl” as used herein denotes an optionally substituted phenyl and naphthyl (e.g. 1-naphthyl, 2-naphthyl or 3-naphthyl), both optionally benz-fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle e.g. to cyclohexyl or cyclopentyl such as 1,2-didehydronaphthyl, 1,2,3,4-tetradehydronaphthyl, anthryl, 1,2-didehydroanthryl, 1,2,3,4-tetradehydroanthryl, phenanthrenyl (e.g. 9- phenanthrenyl), 1,2-didehydrophenanthrenyl or 1,2,3,4- tetradehydrophenanthrenyl.
Suitable substituents for aryl can be selected from those named for alkyl, in addition however, halogen, hydroxy and optionally substituted alkyl, haloalkyl, } alkenyl, alkynyl and aryloxy are substituents which can be added to the selection.
Examples for suitable aryls are tolyl, naphthyl (e.g. 1-naphthyl, 2-naphthyl or 3-naphthyl), p-ethylphenyl, p-propylphenyl, p-(i)propylphenyl, p-butylphenyl, p- (i)butylphenyl, p-(t)butylphenyl, 4-(2-methylpropyl)phenyl, p-hydroxyphenyl, p- fluorophenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, p-methoxyphenyl, p-ethoxyphenyl, p-methylthiophenyl, p-perfluoromethylphenyl, p- perfluoromethoxyphenyl, biphenyl (e.g. 3-biphenylyl or 4-biphenylyl), p- phenoxyphenyl, m-ethylphenyl, m-propylphenyl, m-(i)propylphenyl, m- butylphenyl, m-(i)butylphenyl, m-(t)butylphenyl, m-hydroxyphenyl, m- fluorophenyl, m-chlorophenyl, m-bromophenyl, m-iodophenyl, m- methoxyphenyl, m-ethoxyphenyl, m-methylthiophenyl, m-perfluoromethylphenyl, m-perfluoromethoxyphenyl, m-phenoxyphenyl, o-ethylphenyl, o-propylphenyl, o- (i)propylphenyl, o-butylphenyl, o-(i)butylphenyl, o-(t)butylphenyl, o- hydroxyphenyl, o-fluorophenyl, o-chlorophenyl, o-bromophenyl, o-iodophenyl, o-methoxyphenyl, o-ethoxyphenyl, o-methylthiophenyl, p-methylthiophenyl, o- perfluoromethylphenyl, o-perfluoromethoxyphenyl or o-phenoxyphenyl. Aryl in
R’ is preferably phenyl, naphthyl (e.g. 1-naphthyl, 2-naphthyl or 3-naphthyl), tolyl, phenanthrenyl (e.g. 9-phenanthrenyl), p-ethylphenyl, p-propylphenyl, p- (i)propylphenyl, p-butylphenyl, p-(i)butylphenyl, p-(t)butylphenyl, 4-(2- methylpropyl)phenyl, p-hydroxyphenyl, p-fluorophenyl, p-chlorophenyl, p- bromophenyl, p-iodophenyl, p-methoxyphenyl, p-ethoxyphenyl, p- methylthiophenyl, p-perfluoromethylphenyl, p-perfluoromethoxyphenyl, 3- biphenylyl, 4-biphenylyl, p-phenoxyphenyl, m-ethylphenyl, m-propylphenyl, m- (i)propylphenyl, m-butylphenyl, m-(i)butylphenyl, m-(t)butylphenyl, m- hydroxyphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m- iodophenyl, m-methoxyphenyl, m-ethoxyphenyl, m-methylthiophenyl, m- perfluoromethylphenyl, m-perfluoromethoxyphenyl, m-phenoxyphenyl, o- ethylphenyl, o-propylphenyl, o-(i)propylphenyl, o-butylphenyl, o-(i)butylphenyl, o-(t)butylphenyl, o-hydroxyphenyl, o-fluorophenyl, o-chlorophenyl, o- bromophenyl, o-iodophenyl, o-methoxyphenyl, o-ethoxyphenyl, o- : methylthiophenyl, o-perfluoromethylphenyl, o-perfluoromethoxyphenyl or o- phenoxyphenyl,.
Arylin R% R7, R%, R?, R'? and R" is preferably tolyl, p-ethylphenyl, p- hydroxyphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl,
p-methoxyphenyl, p-ethoxyphenyl, p-perfluoromethylphenyl, p- perfluoromethoxyphenyl, 4-biphenylyl, p-phenoxyphenyl, m-ethylphenyl, m- } hydroxyphenyl, m-fluorophenyl, m-chlorophenyl, m-bromophenyl, m- iodophenyl, m-methoxyphenyl, m-perfluoromethylphenyl, m- perfluoromethoxyphenyl, m-phenoxyphenyl, o-ethylphenyl, o-hydroxyphenyl, o- fluorophenyl, o-chlorophenyl, o-bromophenyl, o-iodophenyl, o-methoxyphenyl, o-ethoxyphenyl, o-methylthiophenyl, o-perfluoromethylphenyl, o- perfluoromethoxyphenyl or o-phenoxyphenyl.
The term “aryloxy” as used herein denotes an aryl group as defined above which is bonded via an oxygen atom. Examples are phenyloxy, naphthyloxy and the like.
Aryloxy in R%, R®, R® and R'? is preferably phenyloxy or naphthyloxy, preferred phenyloxy.
The term “arylthio” as used herein denotes an (aryl)S- group wherein the "aryl" portion is as defined above. Examples are phenylthio or naphthylthio.
Arylthio in R% R® R® and R" is preferably phenylthio or naphthylthio, preferred phenylthio.
The term “heterocyclyl” as used herein denotes an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocyclic systems which contain one or more hetero atoms selected from nitrogen, oxygen and sulfur which can also be fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic carbocycle or heterocycle.
Examples of suitable heterocycles are oxazolyl, isoxazolyl, furyl, tetrahydrofuryl, 1,3-dioxolanyl, dihydropyranyl, 2-thienyl, 3-thienyl, pyrazinyl, isothiazolyl, isoquinolinyl, indolyl, didehydroindolyl, indazolyl, quinolinyl, dihydrooxazolyl, pyrimidinyl, benzofuranyl, tetrazolyl, 1-pyrrolidinyl, 2- pyrrolidinyl, 3-pyrrolidinyl, pyrrolidinonyl, (N-oxide)-pyridinyl, 1-pyrrolyl, 2- pyrrolyl, triazolyl e.g. 1,2,3-triazolyl or 1,2,4-triazolyl, 1-pyrazolyl, 2-pyrazolyl, 4- pyrazolyl, benzotriazolyl, piperidinyl, morpholinyl (e.g. 4-morpholinyl), thiomorpholinyl (e.g. 4-thiomorpholinyl), thiazolyl, pyridinyl, dihydrothiazolyl, imidazolidinyl, pyrazolinyl, benzothienyl, piperazinyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, thiadiazolyl e.g. 1,2,3-thiadiazolyl, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, benzothiazolyl, thianthrene (e.g. 1-thianthrenyl) or heptamethyleneimine, 1,2,4,5-tetrahydro-3H-benzazepin-3-yl, 1,2,3,4-tetrahydro- 2-isoquinolyl, 4-methylpiperazinyl, 1,3,4,5-tetrahydro-2H-benzazepin-2-yl, 2,3- . dihydro-1-indolyl, 2-isoindolinyl, 2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl, 2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl, 8-aminosulphonyl-2,3,4,5-tetrahydro- 1H-2-benzazepin-2-yl, 7-aminosulphonyl-2,3,4,5-tetrahydro- 1H-benzazepin-3-yl, 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl, 1-hexamethyleneimino, 4- hydroxypiperidin-1-yl, 1,2,3,4-tetrahydro-2-isoquinolyl, 4-phenyl-1-piperazinyl.
Suitable substituents for heterocyclyl can be selected from those named for alkyl, in addition however, optionally substituted alkyl, alkenyl, alkynyl, an oxo group (=O) or aminosulphonyl are substituents which can be added to the selection.
Heterocyclyl in R* is preferably unsubstituted or substituted furyl, tetrahydrofuryl, thienyl, indolyl, indazolyl, pyrimidinyl, benzofuranyl, 1- pyrrolidinyl, pyrrolidinonyl, (N-oxide)-pyridinyl, pyrrolyl, piperidinyl, morpholinyl, imidazolyl or benzothiazolyl. Suitable substituents for heterocyclyl in
R? can be selected from unsubstituted or substituted alkyl, unsubstituted or substituted aryl, nitro, cyano and amino.
Heterocyclyl in R is preferably unsubstituted or substituted oxazolyl, isoxazolyl, furyl, tetrahydrofuryl, 1,3-dioxolanyl, dihydropyranyl, thienyl, pyrazinyl, isothiazolyl, isoquinolinyl, 1-indolyl, didehydroindolyl, indazolyl, quinolinyl, dihydrooxazolyl, pyrimidinyl, benzofuranyl, tetrazolyl, 1-pyrrolidinyl, pyrrolidinonyl, (N-oxide)-pyridinyl, 1,2,3,6-tetradehydropyridine, 1-pyrrolyl, 2- pyrrolyl, triazolyl e.g. 1,2,4-triazolyl, 1-pyrazolyl, 2-pyrazolyl, benzotriazolyl, piperidinyl, 4-morpholinyl, 4-thiomorpholinyl, thiazolyl, pyridinyl, dihydrothiazolyl, imidazolidinyl, pyrazolinyl, benzothienyl, piperazinyl, 1- imidazolyl, thiadiazolyl e.g. 1,2,3-thiadiazolyl, benzothiazolyl, 1-thianthrenyl or heptamethyleneimine, 1,2,4,5-tetrahydro-3H-benzazepin-3-yl, 1,2,3,4-tetrahydro- 2-isoquinolyl, 4-methylpiperazinyl, 1,3,4,5-tetrahydro-2H-benzazepin-2-yl, 2,3- dihydro-1-indolyl, 2-isoindolinyl, 2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl, 2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl, 8-aminosulphonyl-2,3,4,5-tetrahydro- 1H-2-benzazepin-2-yl, 7-aminosulphonyl-2,3,4,5-tetrahydro-1H-benzazepin-3-yl, ' 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl, 1-hexamethyleneimino, 4- hydroxypiperidin-1-yl, 1,2,3,4-tetrahydro-2-isoquinolyl, 4-phenyl-1-piperazinyl.
Suitable substituents for heterocyclyl in R’ can be selected from unsubstituted or substituted alkyl as defined above, unsubstituted or substituted . aryl as defined above, nitro, cyano and amino. Examples for substituted heterocyclyl are methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, : 5 butylpiperazinyl, phenylylpiperazinyl, methoxyphenylylpiperazinyl (e.g. 4-(2-
Methoxyphenyl)piperazinyl), ethoxyphenylylpiperazinyl, propyloxyphenylylpiperazinyl, benzo-fused thianthrene or 4-(4-Fluorophenyl)- 1,2,5,6-tetrahydropyridyl.
Heterocyclyl in R® is preferably unsubstituted or substituted oxazolyl, isoxazolyl, furyl, tetrahydrofuryl, 1,3-dioxolanyl, dihydropyranyl, 2-thienyl, 3- thienyl, pyrazinyl, isothiazolyl, isoquinolinyl, indolyl, didehydroindolyl, indazolyl, quinolinyl, dihydrooxazolyl, pyrimidinyl, benzofuranyl, tetrazolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, pyrrolidinonyl, (N-oxide)-pyridinyl, 1,2,3,6- tetradehydropyridine, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1-pyrazolyl, 2- pyrazolyl, 4-pyrazolyl, benzotriazolyl, 1-piperidinyl, 4-morpholinyl, thiomorpholinyl, thiazolyl, pyridinyl, dihydrothiazolyl, imidazolidinyl, 1- imidazolyl, 2-imidazolyl, 4-imidazolyl, pyrazolinyl, benzothienyl, piperazinyl, imidazolyl, thiadiazolyl e.g. 1,2,3-thiadiazolyl, 1,2,3,4-tetrahydroquinoline, 1,2,3,4- tetrahydroisoquinoline, benzothiazolyl, thianthrene or heptamethyleneimine.
Suitable substituents for heterocyclyl in R® can be selected from unsubstituted or substituted alkyl as defined above, unsubstituted or substituted aryl as defined above, nitro, cyano and amino. Examples for substituted heterocyclyl are methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, butylpiperazinyl, phenylylpiperazinyl, methoxyphenylylpiperazinyl, ethoxyphenylylpiperazinyl, propyloxyphenylylpiperazinyl or benzo-fused thianthrene.
Heterocyclyl in R" or R'? is preferably unsubstituted or substituted furyl, tetrahydrofuryl, thienyl indolyl, indazolyl, pyrimidinyl, benzofuranyl, pyrrolidinyl, pyrrolidinonyl, (N-oxide)-pyridinyl, 1-pyrrolyl, piperidinyl, morpholinyl, imidazolyl or benzothiazolyl. Suitable substituents for heterocyclyl in R* can be selected from unsubstituted or substituted alkyl, unsubstituted or substituted aryl, ) nitro, cyano and amino.
The term “heterocyclylamino” refers to a group of formula (heterocyclyl)N(H), wherein heterocyclyl is as defined above. Examples are furylamino, tetrahydrofurylamino, dihydropyranylamino, thienylamino, pyrazinylamino, indolylamino, indazolylamino, quinolinylamino, : benzofuranylamino, pyrrolidinylamino, pyrrolidinonylamino, (N-oxide)- pyridinylamino, pyrrolylamino, pyrazolylamino, benzotriazolylamino, : 5 piperidinylamino, morpholinylamino, thiazolylamino, pyridinylamino, imidazolidinylamino, benzothienylamino, imidazolylamino or benzothiazolylamino.
Heterocyclylamino in R® or R'? is preferably furylamino, tetrahydrofurylamino, dihydropyranylamino, thienylamino, pyrazinylamino, indolylamino, indazolylamino, quinolinylamino, benzofuranylamino, pyrrolidinylamino, pyrrolidinonylamino, (N-oxide)-pyridinylamino, pyrrolylamino, pyrazolylamino, benzotriazolylamino, piperidinylamino, morpholinylamino, thiazolylamino, pyridinylamino, imidazolidinylamino, benzothienylamino, imidazolylamino or benzothiazolylamino.
The term “acyl” as used herein denotes a group of formula C(=O)R wherein
R is hydrogen, an unsubstituted or substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms or a phenyl group. Most preferred acyl groups are those wherein R is hydrogen, an unsubstituted straight chain or branched hydrocarbon residue containing 1 to 4 carbon atoms or a phenyl group.
Acyl in R” and R® (for NR’R®) is independently of each other preferably methylcarbonyl (acetyl), ethylcarbonyl (propionyl), propylcarbonyl, butylcarbonyl or phenylcarbonyl (benzoyl).
The term halogen stands for fluorine, chlorine, bromine or iodine, preferable fluorine, chlorine, bromine.
Halogen in R' is preferably fluorine, chlorine or iodine and more preferred fluorine.
Halogen in Ris preferably chlorine. . Halogen in R’ is preferably chlorine.
Halogen in R®is preferably chlorine or bromine.
Halogen in R'? or R" is preferably fluorine, chlorine , bromine or iodine, more preferred fluorine, chlorine or bromine
Within the invention the term “X” represents O, S or CH,, preferably O or
CH,. Most preferred “X” represents O.
Within the invention the term “Y” represents O, S or NR!!, wherein R!! represents hydrogen, hydroxy or alkyl which denotes an unsubstituted or aryl- substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms. Preferably “Y” represents O, S or NR!! wherein R'! represents hydrogen, hydroxy, phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl.
Within the invention the term “Z” represents O or S, more preferred O.
In the pictorial representation of the compounds given throughout this application, a thickened tapered line (¥) indicates a substituent which is above the plane of the ring to which the asymmetric carbon belongs, a dotted line (---) indicates a substituent which is below the plane of the ring to which the asymmetric carbon belongs, and a wavy line ( ~) indicates a substituent which can be either above or below the plane of the molecule. It is to be understood that the pictorial representation of the compounds given throughout the specification are set forth for convenience and are to be construed as inclusive of other forms including stereoisomers, enantiomers and racemates and are not to be construed as limited to the particular form shown.
Compounds of formula I exhibit stereoisomerism. The compounds of this invention can be any isomer of the compound of formula I or mixtures of these isomers. The compounds and intermediates of the present invention having one or more asymmetric carbon atoms may be obtained as racemic mixtures of stereoisomers which can be resolved, at the appropriate steps in the process of this invention by methods known in the art to obtain a given stereoisomer or pure enantiomer having a desired stereoconfiguration. Alternatively, the desired isomers may be directly synthesised by methods known in the art. : 30 Asymmetric carbon atoms in the compounds of the present invention are denoted as a, b, c and d. The stereoconfiguration of each of the asymmetric carbon atoms denoted as a, b, ¢, and d can be designated according to the particular stereoisomer it represents. Compounds of the present invention include those compounds wherein the carbon atom denoted as “a” has the §, R, or R,S- configuration; the carbon atom denoted as “b” has the S, R, or R,S-configuration; . the carbon atom denoted as “c” has the S, R, or R,S-configuration; and the carbon atom denoted as “d” has the S, R, or R,S-configuration. In a preferred embodiment : 5 of the invention a, b, c and d denoting asymmetric carbon atoms and forming a o-
D, B-D, a-L or B-L ribofuranosyl ring. Preferably a, b, c and d denoting asymmetric carbon atoms and forming an a-D or B-D ribofuranosyl ring and most preferred, B-D ribofuranosyl ring.
Compounds of formula I exhibit tautomerism that means that the compounds of this invention can exist as two or more chemical compounds that are capable of facile interconversion. In many cases it merely means the exchange of a hydrogen atom between two other atoms, to either of which it forms a covalent bond. Tautomeric compounds exist in a mobile equilibrium with each other, so that attempts to prepare the separate substances usually result in the formation of a mixture that shows all the chemical and physical properties to be expected on the basis of the structures of the components.
The most common type of tautomerism is that involving carbonyl, or keto, compounds and unsaturated hydroxyl compounds, or enols. The structural change is the shift of a hydrogen atom between atoms of carbon and oxygen, with the rearrangement of bonds as indicated.
For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form is the predominant one; in phenols, the enol form is the major component. An intermediate situation is represented for example in ethyl acetoacetate, which at room temperature contains about 92.4 percent keto and 7.6 percent enol; at -78° C, the interconversion of the two forms is slow enough for the individual substances to be isolated.
It will be appreciated that within the present invention compounds of formula I exist in various tautomeric forms and that they are encompassed by the present invention.
A preferred embodiment of the invention is the use of compounds of formula I wherein
B signifies a purine base B1 which is connected through the 9-nitrogen of formula
N
N7 NE [as o >—R~ Bi
R* N N wherein
R* R% RS, R’, R® and R’ are as defined in formula I; with the proviso that R* is not NH; and R’ is not NH(CH;); or
B signifies a pyrimidine base B4 which is connected through the 1-nitrogen of formula
R'2 13
N=” :
A I ea
N wherein
Z, R7, R%, R%, R'%, R* are as defined in formula I; with the proviso that R* is not hydroxy, alkoxy, N(CH3),, N(H)NH(CH3) or
N(H)NH; and R" is not hydroxyalkyl, chlorine or bromine; or
B signifies a pyrimidine base B5 which is connected through the 1-nitrogen of formula
Y
RS R'
SN
: A | BS 1
N wherein
Y, Z, R' and R'® are as defined in formula I; with the proviso that R' is not methyl or hydroxyethyl; for the treatment of diseases mediated by the Hepatitis C Virus (HIV) or for the : preparation of a medicament for such treatment.
A further preferred embodiment of the invention is the use of compounds of formula I wherein
R'is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxy or halogen, preferably wherein
R' is hydroxy;
R? is hydrogen, hydroxy, alkoxy, chlorine, bromine or iodine, preferably wherein
R? is hydroxy;
R® is hydrogen; or
R? and R’ represent fluorine;
Xis O; a, b, c and d denoting asymmetric carbon atoms and forming a D-ribofuranosyl ring, preferably wherein a, b, c and d denoting asymmetric carbon atoms and forming a 3-D-ribofuranosyl oo ring; for the treatment of diseases mediated by the Hepatitis C Virus (HIV) or for the preparation of a medicament for such treatment.
Claims (34)
1. Use of compounds of formula I HO a X g-B ra! R RE : 5 wherein R! is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxy, halogen, cyano, isocyano or azido; R?is hydrogen, hydroxy, alkoxy, chlorine, bromine or iodine; Ris hydrogen; or R? and R? together represent =CHa; or : R?and R® represent fluorine; Xis O, S or CHy; a, b, ¢, d denoting asymmetric carbon atoms each of which is substituted with 4 different substituents; and : B signifies 2 purine base B1 which is connected through the 9-nitrogen of formula RS N N el 1 N 5 Ur —R" Bi rR” NN wherein R® is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl, NR'RS, halogen or SH; CLEAN COPY
@® PCT/EP01/09633 oo -177- R’ is hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, heterocyclyl, heterocyclylamino, halogen, NR’R®, NHOR’, NHNR'R® or SH; RS is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl, NR’RE, halo gen, SH or cyano; X R’ and R® are independently of each other hydrogen, alkyl, aryl, hydroxyalkyl, alkenylalkyl, alkynylalkyl, cycloalkyl or acyl; R’ is hydrogen, alkyl or ary}; or B signifies an oxidised purine base B2 which is connected through the 9-nitrogen of formula To — R® - % Pp N 1 PN | D—r B2 R* N N wherein R%, R® and R® are as defined above; or B signifies a purine base B3 which is connected through the 9-nitrogen of formula . Y 0 1 \ 6 PN pe >—R® B3 : RB N “N .
wherein ] R* and R® are as defined above; R'is hydrogen, alkyl or aryl; Yis O,S or NRY; CLEAN COPY
C PCT/EP01/09633 R" is hydrogen, hydroxy, alkyl, OR’, heterocyclyl or NR'R®; 'R’, R® and R® are as defined above; or : . B signifies a pyrimidine base B4 which is connected through the 1-nitrogen of formula B® 13 : N= YY R Ade N wherein ZisOorS; R* is hydrogen, hydroxy, alkyl, alkoxy, haloalkyl, alkylthio, aryl, aryloxy, arylthio, . heterocyclyl, heterocyclylamino, halogen, NR’R®, NHOR’, NHNR’R® or SH; R™ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl or halogen; oo R’, R® and R? are as defined above; or B signifies a pyrimidine base B5 which is connected through the 1-nitrogen of formula vy rR Re ’ SN PN | Bs 1 wherein Y,Z,R19 and R13 are as defined above; for the treatment of diseases mediated by the Hepatitis C Virus (HCV).
2. Use of a compound of formula I as defined in claim 1, in the preparation of a medicament for the treatment of diseases mediated by the Hepatitis C Virus (HCV).
3. Use of compounds of formula I as claimed in claim 1 or claim 2 wherein AMENDED SHEET o PCT/EPO1/09633 i -179 - B signifies a purine base B1 which is connected through the 9-nitrogen of formula Rr
N . N 7 1 h\ 6 Yr »—R® Bl rR“ NTN wherein . R%, R%, R, BR’, R® and R® are as defined in claim 1; with the proviso that R* is not NH, and R’ is not NH(CHs); or : B signifies a pyrimidine base B4 which is connected through the 1-nitrogen of formula Rg" 13 N= R PS | B4 : N wherein Z,R’, R%, R’, RY, R® are as defined in daim 1; with the proviso that R' is not hydroxy, alkoxy, N(CHs),, N(H)NE(CHs) or N(H)NH; and R* is not hydroxyalkyl, chlorine or bromine; or B signifies a pyrimidine base B5 which is connected through the I-nitrogen of formula : Y RC _' SR PN | Bs 1 N wherein Y, Z, R! and R*® are zs defined in daim 1; . - CLEAN COPY with the proviso that R10 is not methyl or hydroxyethyl.
4. Use of compounds of formula I as claimed in any one of claims 1 to 3 wherein R! is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxy, halogen; R? is hydrogen, hydroxy, alkoxy, chlorine, bromine or iodine; R? is hydrogen; or R? and R® represent fluorine; X is O; a, b, c and d denoting asymmetric carbon atoms and forming a D-ribofuranosyl ring.
5. Use of compounds of formula I as claimed in any one of claims 1 to 4 wherein R! is hydroxy; R? is hydroxy; R? is hydrogen; or Xis O; a, b, c and d denoting asymmetric carbon atoms and forming a B-D-ribofuranosyl : ring.
6. Use of compounds of formula I as claimed in any one of claims 1, 2, 4 or 5 wherein B signifies a purine base B1 which is connected through the 9-nitrogen of formula AMENDED SHEET
® PCT/EP01/09633 } ~ -181- : RS : 1 A\ & . fae >—R° Bi R N N wherein R* is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl, NR’R®, halogen or SH; R® is hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, heterocyclyl, heterocyclylamino, halogen, NR’R®, NHOR?, NHNR'R® or : SH; R®is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl, NR'RE, halogen, SH or cyano; R” and R are independently of each other hydrogen, alkyl, aryl, hydroxyalkyl, alkenylalkyl, alkynylalkyl, cycloalkyl or acyl; Lo R’® is hydrogen, alkyl or aryl.
7. Use of compounds of formula I as claimed in any one of claims 1, 2 or 4 to 6 wherein B signifies a purine base Bl which is connected through the 9-nitrogen of formula _ | = 1 N 6 ) PN A >— RB. wherein : R* is hydrogen, chlorine or NHg; Co R® is hydroxy, alkylthio, aryl, heterocyclyl, halogen, NR'R® or SH; AMENDED SHEET
® PCT/EP01/09633 R® is hydrogen, halogen, heterocyclyl or NR'R% 'R” and R® are independently of each other hydrogen, alkyl, aryl, alkenylalkyl or ) alkynylalkyl. ,
8. Use of compounds of formula I as claimed in any one of claims 1, 2 or 4 to 7 wherein B signifies a purine base B1 which is connected through the 9-nitrogen of formula R° oo Yr Yr Bi R N N . wherein : R*is hydrogen; : } R® is alkylthio, aryl, heterocyclyl, halogen or NR7RY; R®is hydrogen or halogen; "Rand R® are independently of each other hydrogen, alkyl, alkenylalkyl or : alkynylalkyl.
9. Use of compounds of formula I as claimed in claim 3 wherein B signifies a purine base Bl which is connected through the 9-nitrogen of formula
R® . 1 AN 6 oY a OY rg NTN AMENDED SHEET
( PCT/EP01/09633 ~ -183- : wherein . * R'is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl, . NR’R®, halogen or SH; , R® is hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, heterocyclyl, heterocyclylamino, halogen, NR'R?, NHOR®, NHNR'R® or SH; R® is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl, NR’R®, halogen, SH or cyano; : R” and R® are independently of each other hydrogen, alkyl, aryl, hydroxyalkyl, : 10 alkenylalkyl, alkynylalkyl, cycloalkyl or acyl; ’ R’ is hydrogen, alkyl or aryl; Co with the proviso that R* is not NH, and R® is not NH(CH;).
10. Use of compounds of formula I as claimed in any one of claims 3 or 9 wherein B signifies a purine base B1 which is connected through the 9-nitrogen of formula . | = NE i A\ 6 [ge Y—r® Bi R* N N wherein R* is hydrogen or chlorine; 2 R®is hydroxy, alkylthio, aryl, heterocyclyl, halogen, NR'R® or SH; RSs hydrogen, halogen, heterocyclyl or NR'RY; AMENDED SHEET
® PCT/EP01/09633 : R’ and R® are independently of each other hydrogen, alkyl, aryl, alkenylalkyl or alkynylalkyl; : with the proviso that R’ is not NH(CHj). ,
11. Use of compounds of formula I as claimed in any one of claims 3, 9 or 10 wherein B signifies a purine base B1 which is connected through the 9-nitrogen of formula RS 1 A\ 6 [ge —R" Bi R* N N wherein R*is hydrogen; So R® is alkylthio, aryl, heterocyclyl, halogen or NR'R®; R® is hydrogen or halogen; R” and R® are independently of each other hydrogen, alkyl, alkenylalkyl or alkynylalkyl; : © 15 with the proviso that R’ is not NH(CH3).
12. Use of a compound of formula I as claimed in claim 1 or claim 2 which compound is 6-Dimethylamino-9-(B-D-ribofuranosyl)purine, 6-[1(S)-Methyl-2-phenylethylamino]-9-(8-D-ribofuranosyl)purine, 3’-Deoxyadenosine, AMENDED SHEET
® PCT/EP01/09633
6-(Phenylethylamino)-9-(B-D-ribofuranosyl)purine, 6-(Cydlohexylamino)-9-(B-D-ribofuranosyl)purine, 2-Chloroadenosine, . 9-(B-D-Ribofuranosyl)purine, 8-Bromoadenosine, 8-Bromo-2’-deoxyadenosine, 8-Bromoguanosine, ] 6-Thioinosine, 6-Methylthio-9-(B-D-ribofuranosyl)purine, 6-Chloro-9-(B-D-ribofuranosyl)purine, 2-Amino-6-chloro-9-(B-D-ribofuranosyl)purine, 6-(N-Methylpropylamino)-9-(B-D-ribofuranosyl)purine, 9-(B-D-Ribofuranosyl)-6-(4-thiomorpholinyl)purine, 6~-(N-Methyl-2-propenylamino)-9-(f-D-ribofuranosyl)purine,
6-(N-Methyl-2-propynylamino)-9-(8-D-ribofuranosyl) purine, 6-(4-Morpholinyl)-9-(B-D-ribofuranosyl)purine, 6-Diethylamino-9-(B-D-ribofuranosyl)purine, 6-(1(R.S)-Phenylethylamino)-9-(-D-ribofurznasyl)purine,
* 6-(1-Benzyl-1-methylethylamino)-9- (B-D-ribofurancsyl)purine, 6-(3-Phenylpropylamino)-9-(B-D-ribofuranosyl)purine, CLEAN COPY
® PCT/EP(01/09633
9-(B-D-Ribofuranosyl)-6-[2-(2-thienyl)ethylamino]purine, 6-Dibenzylamino-9-(B-D-ribofuranosyl)purine, 6-Hexylamino-9-(B-D-ribofuranosyl) purine, 6-(3-Pyridylmethylamino)-9-(B-D-ribofuranosyl)purine, 6-[4-(4-Fluorophenyl)-1,2,5,6-tetrahydropyridyl]-9-(B-D-ribofuranosyl)purine, 6-[4~(2-Methoxyphenyl) piperazinyl]-9-(8-D-ribofuranosyl)purine, 6- (2-(3-Indolyl)ethylamino]-9-(B-D-ribofiuranosypuine, 6-[2-(4-Chlorophenyl)ethylamino)]-9-(f-D-ribofuranosyl)purine, 6-(N-Methylphenylamino)-9-(f-D-ribofuranosyl)purine,
9-(B-D-Ribofuranosyl)-6-(1,2,4,5-tetrahydzo-3H-benzazepin-3-f)purine, 9-(B-D-Ribofuranosyl)-6-(1,2,3,4-tetrahydro-2-isoquinolyl)purine, 6-(4-Methylpiperazinyl)-9-(B-D-ribofuranosyl)purine, 9-(B-D-Ribofuranosyl)-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)purine, 6-[2-(4-Cyanomethylphenyl)ethylamino] Dressage,
6-(2,3-Dihydro-1-indolyl)- 9-(B-D-ribofuranosyl)purine, : 9-(B-D-Ribofuranosyl)-6-(2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl) purine, 9-(B-D-Ribofuranosyl)-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl)purine, 6-(8-Aminosulphonyi-2,3,4,5- tetrahydro-1H-2-benzazepin-2-y1)-9-( 8.1. ribofuranosyl)purine,
6-[2-(3,4-Dimethoxyphenyl)ethylamino)-9-(8-D-ribofuranosyl) purine,
CLEAN COPY
® PCT/ER01/09633
6-[-2-(4-Hydroxyphenyl)ethylamino]-9-(B-D-ribofuranosyl)purine, 6-(2-Isoindolinyl)-9-(B-D-ribofuranosyl)purine, 6-(7-Aminosulphonyl-2,3,4,5-tetrahydro-1H-benzazepin-3-yl1)-9-(B-D- ribofuranosyl)purine,
6-(N-Cyclohexylmethylamino)-9-(B-D-ribofuranosyl)purine, 6-(N-Hexylmethylamino)-9-(B-D-ribofuranosyl)purine, 6-(10,11-Dihydro-5H-dibenzo[a,d} cyclohepten-5-ylamino)-9-(B8-D- ribofuranosyl)purine, 6-[N-(10,11-Dihydro-5H-dibenzo[a,d] cyclohepten-5-yl)methylamino}-9-(f-D- ribofuranosyl)purine, 6- [N-(5-Aminopentylymethylamino}--(-D-ribofizanosyl)puzine, 6-[(5-Chloro-2-methoxyphenyl)methylamino)]-9-(B-D-ribofuranosyl)purine, 6-{(2-Methylphenyl)methylarine]-9-(B-D-ribofuranosyl) purine, 6-(Hexamethyleneimino)-9-(f-D-ribofuranosyl)purine, 6-(1-Pyrrolidinyl)-9-(f-D-ribofuranosyl)purine, 6-(4-Hydroxypiperidin-1-y1)- 9-(B-D-ribofuranosyl)purine, 6-(1-Piperidinyl)-9-(B-D-ribofuranosyl)purine, : 6-(2-Propenyl)amino-9-(B-D-ribofuranosyl)purine, 6-(2-Propynyl)amino-9-(B-D-ribofuranosyl)purine, 6-(1-Methyl)ethylamino-9-(B-D-ribofuranosyl)purine, 6-bis-(2-Propenyl)amino-9-(B-D-ribofuranosyl)purine, CLEAN COPY
C PCT/EP01/09633 6-(2-Phenylethyl)methylamino-9-(B-D-ribofuranosyl)purine, 6-Ethylmethylamino- 9-(B-D-ribofuranosyl)purine, 6-bis-[(3-Methyl)butylamino]-9-(B-D-ribofuranosyl)purine, 6-(4~Aminophenyl)methylamino-9-(f-D-ribofuranosyl)purine, 6~(2-Pyridylmethyl)amino-9-(B-D-ribofuranosyl)purine, 6-(2-Hydroxyethyl)methylamino-9-(B-D-ribofuranosyl)purine, 6-Dipropylamino-9-(B-D-ribofuranosyl)purine, 6-[2-Phenyl-(N-propionyl)ethylamino}-9-(fB-D-ribofuranosyl) purine, 6-(N-Benzoyl-2-phenylethylamino)-9-(f8- D-ribofuranosyl)purine, 2-Amino-6-methylamino-9-(B-L-ribofuranosyl)purine, 2-Amino-6-methylamino-9-(f-D-ribofuranosyl)purine, 2-Amino-6-(4-morpholinyl)-9-(B-D-ribofuranosyl)purize, 2-Amino-6-(1-pyrrolidinyl)-9-(B-D-ribofurancsyl)purine, 2,6-Diamino-9-(B-L-ribofuranosyl) purine,
2.6-Distaino-9-(B-D-rbofaranosylypuzine, 2-Chloro-6-(1-pyrrolidinyl)-9-(B-D-ribofuranosyl)purine, 2-Chloro-6-(1-hexamethyleneimino)-9-(B-D-ribofuranosyl)purine, 2-Chloro-6-(4-hydroxy-1-piperidinyl)-9-(B-D-ribofuranosyl)purine,
6.-|(N-Cydlobexyl)methylamino] -2- methylthio-9-(B-D-ribofuranosyl)purine, 6~(1-Pyrrolyl)-9-(B-D-ribofuranosyl)purine, CLEAN COPY
® PCT/EPQ1/09633
6-(1-Pyrrolyl)-9-(B-D-arabinofuranosyl) purine, 6-(1-Pyrrolyl)-9~(B-D-ribofuranosyl)purin-8-(7H)-one, 9-(3-Deoxy-f3-D-ribofuranosyl)-6-(1-pyrrolyl) purine, 6-(1-Pyrrolyl)-9~(B-L-ribofuranosyl)purine, 6-(1-Indolyl)-9-(B-D-ribofuranosyl)purine, | :
6-(1-Imidazolyl)-9-(B-D-ribofuranosyl)purine, E
9-(B-D-Ribofuranosyl)-6-(1,2,4-triazol-1-yl)purine, 6-(1-Pyrazolyl)- 9-(B-D-ribofuranosyl) purine, 9-(B-D-Ribofuranosyl) 6-(1,2,4~triazol-4-yl)purine,
6-Methylamino-9-($-D-ribofuranosyl)purin-2( 1H)-one, ; 2-Methoxy-6-methylamino-9-(B-D-ribofuranosyl)purine,
»-Methoxyadenosine, 2,6-Dichloro-9-(B-D-ribofuranosyl)purine, 6-Methoxy-S-(B-D-ribofuranosyl)purine,
2-Amino-6-benzylthio-9-(f-D-ribofuranosyl) purine, - 6-Benzylthio-2-hydroxy-9-(B-D-ribofuranosyl)purine, 9-(B-D-Ribofuranosyl)purine-2,6,8(1H,3H,7H)-trione, 8-(Methylamino adenosine, 8-(2-Phenylethylamino)adenosine,
8-Benzylaminoadenosine, .
CLEAN COPY
[ PCT/EP01/09633
8-(1-Piperidinyl)adenosine, ] '8-(Dimethylamino)adenosine, 8-(3-Phenylpropylamino)adenosine, 8-(4-Morpholinyl)adenosine, 8-(N-Methyl-2-phenylethylamino)adenosine, 8-(3-Pyridylmethylamino)adenosine, 8-(Ethylamino)adenosine, : : 8-(1,2,3,4-Tetrahydro-2-isoquinolyl)adenosine, 8-[2-(4-Morpholinyl)ethylamino]adenosine, 8-(Hexylamino)adenosine, 8-(2-Cyclohexylethylamino)adenosine, 8-(2(R,S)-Phenylpropylamino)adenosine, 8-[2-(4-Methylphenyl) ethylamino}adenosine, 8-[2-(1-methyl-2-pyrrolyl) ethylamino]adenosine, - 8-[2-(4-Aminosulphonylphenyl) ethylamino]adenosine, : 8-(4-Phenyl-1-piperazinyi)adenosine, . 8-(2-(4-Imidazolyl)adenosine, 8-(1-Naphthylmethylamino)adenosine, 8-[2-(4-Hydroxyphenyl)ethylamino]adenosine, 8-(4-Phenylbutylamino)adenosine, 8-[2-(4-Chloropheny!)ethylamino]adenosine, 8-[2-(2,4-Dichlorcphenyl)ethylamino}adenosine, CLEAN COPY
[ PCT/EP01/09633
8-(2-Propenylamino)adenosine, ] * 8-(2-Hydroxyethylamino)adenosine, 8-(1(R)-Methyl-2-phenylethylamino)adenosine, 8-(4-Fluorobenzylamino)adenosine, 8 [(4-Hydsoxycarbonyl)benzylamino]adenosine, 8-(2-Propynylamino)adenosine, 8-(1-Methylethylamino)adenosine,
8-[(4-Trifluoromethyl)benzylaminojadenosine, 8-[(2,5-Dimethoxy)benzylamino]adenosine, 8-[2-(2-Thienyl)ethylamino]adenosine, 8-[2-(4-Aminophenyl)ethylamino]adenosine, : 8-(2-Phenoxyethylamino)adenosine, 8-[(2-Thienyl)methylamino)adenosine, 8-[(4-tert-Butyl)benzylamino]adenosine, 8-(1(R)-Phenylethylamino)adenosine, : 8-(1(S)-Phenylethylamino)adenosine, 8-(6-Phenylhexylamino)adenosine, 8-[2-Hydroxy-1(S)-phenyl)ethylamino]adenaosine, 2’-Deoxy-8-(2-phenylethylamino)adenosine, 2’-Deoxy-8-(3-phenylpropylamino)adenosine, 8-Benzylamino-2’-deoxyadenosine, 2’-Deoxy-8-(4-phenylbutylamino)adenosine, CLEAN COPY
@ PCT/EP01/09633 2’-Deoxy-8-(6-phenylhexylamino)adenosine, : * 8-(4-Morpholinyl)inosine, 8-(Methyithio)adenosine, . 8-(Benzylthio)adenosine, 8-(Benzyloxy)adenosine, } 8-Ethoxyadenosine, 8-[(1-Hydroxy-1-methyl)ethyl}adenosine, 9-(B-D-ribofuranosyl)-6-(3-thienyl)purine, 6-Phenyl-9-(B-D-ribofuranosyl) purine, 6-(4-Fluorophenyl)-9-(f-D-ribofuranosyl) purine, 6-(4-Chlorophenyl)-9-(8-D-ribofuranosyl) purine, 6-(4-Methylphenyl)-9-(B-D-ribofuranosyl) purine,
6. (4 Methoxyphenyl)-9-(B-D-ribofuranosyl) purine, 9-(B-D-Ribofuranosyl)-6-(1-thianthrenyl)purine, 6-(4-Biphenylyl)-9-(B-D-ribofuranosyl) purine, 6-(4-Methylthiophenyl)-9-(B-D-ribofuranosyl) purine, 6-(2-Methylphenyl)-9-(B-D-ribofuranosyl) purine, 6-(9-Phenanthrenyl)-9-(B-D-ribofuranosyl purine,
6.(8-D-Ribofuranosyl)-6-(3-trifizoromethylphenyl)purine, 6-(2-Phenoxyphenyl)-9-(B-D-ribofuranosyl) purine, CLEAN COPY
® PCT/EP(1/09633 ‘ 6-(4-tert-Butylphenyl)-9-(B-D-ribofuranosyl) purine, : 9-~(B-D-Ribofuranosyl)-6-(2-trifluoromethoxyphenyl)purine, 6-(4-Phenoxyphenyl)-9-(B-D-ribofuranosyl)purine, 6-(3-Methoxyphenyl)-9-(8-D-ribofuranosyl) purine, 6-(2-Naphthyl)-9-(B-D-ribofuranosyl)purine, : 6-(3-Biphenylyl)-9-(8-D-ribofuranosyl)purine, 6-[4-(2-Methylpropyl)phenyl]-9-(B-D-ribofuranosyl purine, 6-(3-Fluorophenyl)-9-(B-D-ribofuranosyl)purine, 9-(8-D-Ribofuranosyl)-6-(4-trifluoromethylphenyl)purine, 6-(3- Ethoxyphenyl)-9-(B-D-ribofuranossl)purine, 6-[3-(1-Methyl)ethylphenyi]-9-(B-D-ribofuranosyl)purine, 9-(B-D-ribofuranosyl)-6-(4-trifluoromethoxyphenyl)purine,
6. (4-Exhylphenyi)-5-(3-D-ribofursnossl)purine, 2-Amino-6-phenyl-9-(B-D-ribofuranosyl) purine, 6-Ethylamino-9-(f-D-ribofuranosyl)purine, or 6-Propylamino-9-(f-D-ribofuranosyl)purine. i
13. Use of compounds of formula I as claimed in any one of claims 1 to 5 wherein : B signifies an oxidised purine base B2 which is connected through the 9-nitrogen of formula : : AMENDED SHEET
® | PCT/EP01/09633 I 1 N 3 PN Dr B82 R* N N wherein R*is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl, NR’R?, halogen or SH; R’ is hydrogen, hydroxy, alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, aryl, aryloxy, aryithio, heterocyclyl, heterocyclylamino, halogen, NR'R®, NHOR’, NHNR'R® or : SH; E RS is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl, - NRRS, halogen, SH or cyano; R” and R? are independently of each other hydrogen, alkyl, aryl, hydroxyalkyl, alkenylalkyl, alkynylalkyl, cycloalkyl or acyl; : R? is hydrogen, alkyl or aryl.
14. Use of compounds of formula I as claimed in any one of claims 1 to 5 or 13 wherein R*is hydrogen; R® is hydrogen, alkyl, heterocyclyl or NR’RY; R® is hydrogen; R” and R?® are independently of each other hydrogen, alkyl, aryl, hydroxyalkyl, alkenylalkyl, alkynylalkyl, cycloalkyl or acyl.
15. Use of a compound of formula I as claimed in any one of claims 1 to 5 or 13 which compound is AMENDED SHEET
® PCT/EP01/09633 Adenosine-1-oxide, or * 6-(2-Phenylethylamino)- 9-(B-D-ribofuranosyl)purine-1-oxide.
16. Use of compounds of formula I as claimed in any one of claims 1 to 5 wherein . B signifies a purine base B3 which is connected through the 9-nitrogen of formula Y R'U N N 6 On B3 r NTN wherein R*is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl, NR’R®, halogen or SH; : R® is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, aryloxy, arylthio, heterocyclyl, NR'R, halogen, SH or cyano; R’ and R® are independently of each other hydrogen, alkyl, aryl, hydroxyalkyl, alkenylalkyl, alkynylalkyl, cycloalkyl or acyl; R® is hydrogen, alkyl or aryl; | - RY is hydrogen, alkyl or arvl; Y is O,.S or NRM; | : R™ is hydrogen, hydroxy, alkyl, OR’, heterocydiyl or NR'R®. Co
17. Use of compounds of formula I as claimed in any one of claims 1 to 5 or 16 wherein AMENDED SHEET
® PCT/EP01/09633 B signifies a purine base B3 which is connected through the $-nitrogen of formula : vy 10 " YX Nr B3 ~ 9 : R* N N R* is hydrogen, NR'R" or hydroxy; R® is hydrogen, halogen or NR'R?; - R’ and R? are independently of each other hydrogen or alkyl; : RY is hydrogen or alkyl; | : a. Y is O, S, NH or N-alkyl.
18. Use of a compound of formula I as claimed in claim 1 or claim 2 which compound is 3’-Deoxyguanosine, 6-Thioguanosine, Inosine, L-Inosine, a 8-Bromoinosine, - : 1-Benzyl-6-imino-9-(B-D-ribofuranosyl)purine, cL 1-Methyi-6-(2-phenylethylimino)-9-(B-D-ribofuranosyl)purine, 2-(Acetylamino)inosine, or 8-(Benzylamino)inosine. ; AMENDED SHEET
() | PCT/EP01/09633
19. Use of compounds of formula I as claimed in any one of claims 1, 2, 4 or wherein B signifies a pyrimidine base B4 which is connected through the 1-nitrogen of formula R'2 13 NANT PS | Ba 5 N ‘wherein . ] : ZisQorS; R" is hydrogen, hydroxy, alkyl, alkoxy, haloalkyl, alkylthio, aryl, aryloxy, aryithio, heterocyclyl, heterocyclylamino, halogen, NR'R®, NHOR’, NHNR’R® or SH;
10 . RY is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl or halogen; R” and R® are independently of each other hydrogen, alkyl, aryl, hydroxyalkyl, alkenylalkyl, alkynylalkyl, cycloalkyl or acyl; R’ is hydrogen, alkyl or aryl.
20. Use of compounds of formula I as claimed in any one of claims 1, 2, 4, 5 or 19 wherein B signifies a pyrimidine base B4 which is connected through the I-nitrogen of formula R'2 13 NPN PN 1 | B4 : N wherein AMENDED SHEET
@® PCT/EPQ1/09633 ZisO; * R'is hydroxy, alkyl, heterocyclyl, NR'R®, NHOR®, heterocyclylamino, NHNR'R® or SH; R* is hydrogen, alkyl or halogen; R’ and R® are independently of each other hydrogen, alkyl, aryl, hydroxyalkyl, h alkenylalkyl, alkynylalkyl, cycloalkyl or acyl; : R’ is hydrogen, alkyl or aryl.
21. Use of compounds of formula I as claimed in any one of claims 1, 2, 4, S, 19 or 20 wherein B signifies a pyrimidine base B4 which is connected through the 1-nitrogen of formula } R'? : 13 N“ R PN | B4 N wherein Zis G; R*? is hydroxy, alkyl or NR'R% RY is hydrogen; . R” and R® are independently of each other hydrogen or alkyl.
22. Use of compounds of formula I as claimed in claim 1 or claim 2 wherein R! is hydrogen, halogen, hydroxy, alkyl, alkoxy, cyano or azido; AMENDED SHEET
® ~ PCT/EP01/09633 R? is hydrogen or hydroxy; or ] | E ' R? and R® represent fluorine; : XisOor CHy a,b,c, d denoting asymmetric carbon atoms each of which is substituted with 4 different substituents; and B signifies a pyrimidine base B4 which is connected through the 1-nitrogen of : formula : ’ R'2 A ; | B84 N wherein ) Zis Os i Ris NR'R®; R" is hydrogen, alkyl or halogen; R’ and R® are independently of each other hydrogen or alkyl.
23. Use of compounds of formula I as claimed in any one of claims 1 or 2 or 22 wherein R! is hydrogen, fluorine, hydroxy, C,4-alkyl, Ci4-alkoxy, cyano or azido; . R? is hydrogen or hydroxy; or R% and R® represent fluorine; xX isOor CH; a, b, ¢, d denoting asymmetric carbon atoms each of which is substituted with 4 different substituents; and AMENDED SHEET
@® | PCT/EP01/09633 B signifies a pyrimidine base B4 which is connected through the 1-nitrogen of formula R™2 13 : N= R PN | Bs N wherein : Zis O; R™is NR'R% R* is hydrogen, C; s-alkyl or fluorine; R? and R® are independently of each other hydrogen or C;4-alkyl.
24. Use of compounds of formula I as claimed in claim 3 wherein B signifies a pyrimidine base B4 which is connected through the I-nitrogen of : formula : R'2
13 . NF R AN | B4 N wherein ZisOor$; R'is hydrogen, alkyl, haloalkyl, alkylthio, aryl, aryloxy, arylthio, heterocyclyl, heterocyclylamine, halogen, NR’R®, NHOR®, NHNRRE or SH; R" is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl or halogen; AMENDED SHEET
¢® PCT/EP01/09633 : R’ and R® are independently of each other hydrogen, alkyl, aryl, hydroxyalkyl, alkenylalkyl, alkynylalkyl, cycloalkyl or acyl; Co R’ is hydrogen, alkyl or ary}; with the proviso that R'? is not N(CHs),, N(H)NH(CH;) or N(H)NH, and R” is not hydroxyalkyl, chlorine or bromine. .
25. Use of compounds of formula I as claimed in any one of claims 3 or 24 wherein B signifies a pyrimidine base B4 which is connected through the I-nitrogen of : formula : ) R2 13 NZ R PN , | Ba
N . wherein —- Zis O; R*? is alkyl, heterocyclyl, NR'R?, NHOR?, heterocyclylamino, NEINR’R® or SH; ) 15 RY is hydrogen, alkyl or halogen; R’ and R® are independently of each other hydrogen, alkyl, aryl, hydroxyalkyl, alkenylalkyl, atkynylalkyl, cycloalkyl or acyl; : R’ is hydrogen, alkyl or aryl; with the proviso that R'? is not N(CH)a, N(H)NH(CHs) or N(H)NHE; and R*is - not hydroxyalkyl, chlorine or bromine. AMENDED SHEET o PCT/EP01/09633 : 26., Use of compounds of formula I as claimed in any one of claims 3, 24 or 25 : wherein B signifies a pyrimidine base B4 which is connected through the l-nitrogen of formula R'2 13 N= R AN | | B4 N wherein Zis O; RY is alkyl or NR'RS; R" is hydrogen; _ R’and Rare independently of each other hydrogen or alkyl; : with the proviso that R' is not N(CH), N(H)NH(CHs) or N(H)NH,.
27. Use of a compound of formula I as claimed in claim 1 or claim 2 which compound is 4-Thiouridine, oo 5-Fluorocytidine, 1-(B-D-arabinofuranosyl)-5-fluorocytosine, 5-Methylcytidine, : 2’,3’-Dideoxycytidine, . N4-Acetylcytidine, } 3’-Deoxycytidine, AMENDED SHEET :
@® PCT/EP01/09633 4-Methoxy-1-(B-D-ribofuranosyl)pyrimidin-2(1H)-one, &-Methylthio-1-(B-D-ribofuranosy] )pyrimidin-2(1H)-one, 5-Fhuoro-4-methylthio-1-(B-D-ribofuranosyl)pyrimidin-2( 1H)-one, 5-Methyl-4-methylthio-I-(B-D-ribofurancsyl)pyrimidin-2(1H)-one, 3 -Azido-23 dideoxy 5-methylcytidine, 1-(3-Deoxy-B-L-threo-pentofuranosyl)-5-fluorocytosize, 4-Methylamino-1-(-D-ribofuranosyl)pyrimidin-2(1H)-one,5-Fluoro-4-methylamino- 1-(f8-D-ribofuranosyl )pyrimidin-2(1H)-one, 4-(1-Pyrrolyl)-1-(B-D-ribofuranosyl)pyrimidin-2( 1H)-one, . 1-(2-Deoxy-2,2-difluoro-B-D-erythropentofuranosyl)cytosine, 4 Amino-1(R)-(2(S)3(R)-dilydroxy-4(R)-hydroxymethyl-cydopentyl)- 1H- pyrimidin-2-one, . 1-(B-D-Xylofuranosyl)cytosine, 1(3-Deoxy-3-fiuoro-B-D-xylofurancsyl)cytosine, or 3’-Deoxy-3"-hydroxymethylcytidine.
28. Use of compounds of formula I as claimed in claim 3 wherein R! is hydrogen, halogen, hydroxy, alkyl, alkoxy, cyano or azido; } Ris hydrogen or hydroxy; or . R? and R® represent fluorine; X is O or CHz; AMENDED SHEET
@® PCT/EP01/09633 a,b, ¢, d denoting asymmetric carbon atoms each of which is substituted with 4 different substituents; and B signifies a pyrimidine base B4 which is connected through the 1-nitrogen of . formula R'2 13 NZ R AN 1 | | B4 N wherein : . Zis O; RY is NR'R%; R* is hydrogen, alkyl or halogen; R’ and R® are independently of each other hydrogen or alkyl; ! with the proviso that RY is not N(CHa); and R® is not chlorine or bromine.
29. Use of compounds of formula I as claimed in claim 3 or claim 28 wherein R'is hydrogen, fluorine, hydroxy, C;4-alkyl, C;4-alkoxy, cyano or azido; R? is hydrogen or hydroxy; or R?and R® represent fluorine; X is O or CHy; a, b, ¢, d denoting asymmetric carbon atoms each of which is substituted with 4 different substituents; and B signifies a pyrimidine base B4 which is connected through the 1-nitrogen of formula AMENDED SHEET
® PCT/EPOL/09633 RZ 13 : NZ R Pe | Ba N wherein ’ Zis QO; R'is NR'R% R* is hydrogen, C;.4-alkyl or fluorine; : R’ and R® are independently of each other hydrogen or Cy4-alkyl; with the proviso that R* is not N(CHs),. :
30. Use of a compound of formula I as claimed in any one of claims 1, 2, 22, 23, 28 or 29 which compound is L-Cytidine, or 4-Amino-1-(2,2-difluoro-3-hydroxy-4-hydroxymethyl-cyclopentyl)- 1 H-pyrimidin-2-
one.
31. Use of compounds of formula I as claimed in any one of claims 1, 2, 4 or 5 wherein B signifies a pyrimidine base BS which is connected through the 1-nitrogen of formula Y R'2 J rR"
SN . PN ji BS N AMENDED SHEET
@ PCT/EP01/09633 wherein } : Yis 0, Sor NR; ZisOorS; RY is hydrogen, alkyl or aryl; RY is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl or halogen.
32. Use of compounds of formula I as claimed in any one of claims 1 to 5 or 31 wherein B signifies a pyrimidine base B5 which is connected through the 1-nitrogen of formula : v . : RY Re . SN PS | 85 1 R N wherein . Y is O or NR"; : Zis O; R¥is hydrogen; a R'is hydrogen, alkyl or halogen.
33. Use of compounds of formula I as claimed in claim 3 wherein B signifies a pyrimidine base BS which is connected through the 1-nitrogen of formula AMENDED SHEET
( PCT/EPO1/09633 I R'2 R' aN PN | B5 1 N wherein Yis O, S or NR"; ZisQorS; R' is hydrogen, alkyl or aryl; oo R® is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl or halogen; : with the proviso that R'° is not methyl or hydroxyethyl.
34. Use of a compound of formula I as claimed in claim 1 or claim 2 which compound is 2’-Deoxy-5-fluorouridine, 1-(B-D-Arabinofuranosyl) -5-fluorouracil, 5-Fluorouridine, 5-Bromouridine, : 3-Methyluridine, . : 5-Methyluridine, 1-( B-D-Arabinofuranosyl)uracil, 1-(B-D-Arabinofuranosyl)-5-methyluracil, 1-(B-D-Arabinofuranosyl)-5-iodouracil, "3’-Deoxy-5-methyluridine, 5-Ethyluridine, AMENDED SHEET
@® PCT/EP01/09633
5-[(1-Methyl)ethyl]uridine, ) :
5-Methoxymethyluridine, 5-Ethoxymethyluridine, 5-Chlorouridine,
5-Methyl-1-(8-L-ribofuranosyl uracil, 1-(B-D-Arabinofuranosyl)-5-ethyluracil, 1- (B-D-Arabinofuranosyl)-5-bromo uracil, 5-Methyl-4-thiouridine, 5-Fluoro-4-thiouridine,
1-(2-Deoxy -0-D-erthyro-pentofuranosyl)-5-fluorouracil, 2-Deoy-5-finoro-3-methyiuridine, 1-(a-D-Erthyro-2-deoxypentofuranosyl)-5-fluoro-3-methyluracil, 2’-Chloro-2’-deoxyuridine, 2’-Bromo-2’-deoxyuridine,
1-(2-Deoxy-B-D-lyxofuranosyl)-5-methyluracil, 3’-Deoxy-3’-fluoro-5-methyluridine, 2’,3’-Dideoxy-5-ethyl-3’-methoxyuridine, 5’-Benzyloxy-2’,3’-dideoxy-5-methyluridine, 2’,3’-Dideoxy-5-ethyl-3’-iodouridine,
3-Azido-2',3-dideoxy-5-ethyluridine, - 4-Oximino-1-{B-L-ribofuranosyl)pyrimidin-2(1H)-one,
CLEAN COPY
C PCT/EP01/09633 4-Oximino-1-(f-D-ribofuranosyl)pyrimidin-2(1H)-one, : 4-Oximino-1-(B-D-arabinofuranosyl)pyrimidin-2(1H)-one, 5-Fluoro-4-oximino-1-(f-D-ribofuranosyl)pyrimidin-2(1H)-one, 1-(2-Deoxy-2,2-difluoro-a-D-erythropentofuranosyl uracil, 1-(3-Deoxy-3-fluoro-f-D-xylofuranosyl Juracil, or 2’-Deoxy-2’-methoxyuridine.
35. Compounds of formula I-a HO a xX a B’ . b' [od I-a : . R" R? wherein : R® is hydroxy; R? is hydroxy; - Xis0; a’, b’, ¢, @ denoting asymmetric carbon atoms and forming 2 D-ribofuranosyl ring; and B’ signifies an oxidised purine base B2-a which is connected through the 9- nitrogen of formula AMENDED SEEET
® : PCT/EP01/09633 ] RE : 0, NL 1 Jd PN | D>—r B2a RY N N wherein R* is hydrogen; R®”isNHRY; R® is hydrogen; } R® is alkyl; hydrolyzable esters or ethers thereof and pharmaceutically acceptable salts thereof.
36. A compound as claimed in claim 35 which compound is selected from: 6-(2-phenylethylamino)-9-(8-D-ribofuranosyl)purine-1-oxide.
37. Compounds of formula I-b HO a” X a B* bp” c” I-b : RR wherein RY” is hydroxy; R*” is hydroxy; X”is Os : AMENDED SHEET
( PCT/EP01/09633 a”, b”, ¢”, d” denoting asymmetric carbon atoms and forming a D-ribofuranosyl ring; and Co B” signifies a purine base B3-a which is connected through the 9-nitrogen of formula : Y” 10” : 1 A\ &” _ IS | : S>—n B3-a a/ SN R wherein ’ R*’ is hydrogen; R®’ is hydrogen; R™® is alkyl; is NR’; : RM is alkyl; } hydrolyzable esters or ethers thereof and pharmaceutically acceptable salts thereof.
38. A compound as claimed in claim 37 which compound is selected from: 1-Methyl-6-(2-phenylethylamino)-9-(8-D-ribofuranosyl)purine.
39. Compounds of formula I-c HO a” X an B™ . b” Jem Ic RR" AMENDED SHEET
( PCT/EP01/09633 wherein i - RY” is hydroxy; R®” is hydroxy; X7is 0; a’, b’”, ¢’”, d””’ denoting asymmetric carbon atoms and forming a D- ribofuranosyl ring; and : : group B’” signifies a pyrimidine base B4-a which is connected through the 1- nitrogen of formula So : RZ i ou A ; B4-a . Zz" N™ wherein : R'#” is alkylthio or heterocyclyl; R'is hydrogen, alkyl or halogen; 2” is 0 hydrolyzable esters or ethers thereof and pharmaceutically acceptable salts thereof.
40. Compounds as claimed in claim 39 which compounds are : 5-Fluoro-4-methylthio- 1-(B-D-ribofuranosyl)pyrimidin-2(1H)-one, 5-Methyl-4-methylthio-1-(B-D-ribofuranosyl)pyrimidin-2(1H)-one, or 4-(1-Pyrrolyl)-1-(B8-D-ribofuranosyl)pyrimidin-2(1H)-one. AMENDED SHEET
( | PCT/EP01/09633
: 41. Compounds of formula I-d ) HO a” xX is) B™ h™ o™ I-d R* RR wherein : RY is hydrogen, halogen, hydroxy, alkyl, alkoxy, cyano or azido; R**” and R*™ represent fluorine; X” is O or CHa; a””,b””, ¢””, d”” denoting asymmetric carbon atoms each of which is substituted with 4 different substituents; and group B””” signifies 2 pyrimidine base B4-b which is connected through the 1- nitrogen of formula RZ" 13™ : N= R Au | Bab ZF N wherein rididd is QO; . . Ri» is NR? R®™ RY” is hydrogen, alkyl or halogen; R7”” and R®"” are independently of each other hydrogen or alkyl; hydrolyzable esters or ethers thereof and pharmaceutically acceptable salts thereof.
AMENDED SHEET :
® | PCT/EP01/09633
42. Compounds of formula I-d as claimed in claim 41 . wherein R*” is hydrogen, fluorine, hydroxy, C,q-alkyl, Cy 4-alkoxy, cyano or azido; X” is CHy; and group B”” signifies a pyrimidine base B4-b which is connected through the 1- nitrogen of formula : RZ” : 13" NZ R A , | Bab Zz” N wherein R™ is hydrogen, Ci.¢-alkyl or fluorine; R™” and R*"” are independently of each other hydrogen or C;4-alkyl.
43. Compounds as claimed in claims 41 or 42 which compound is : 4-Amino-1-(2,2-difluoro-3-hydroxy-4-hydroxymethyl-cyclopentyl)-1H- pyrimidin-2-one.
44. Compounds of formula I-e :
- . . HO am Xm B™ pr fy I-e : RR wherein AMENDED SHEET
[ PCT/EP01/09633 RY” is alkoxy; © R®”” is hydrogen; XX” is 03 a?” pb”, £7”, 4” denoting asymmetric carbon atoms and forming a D- ribofuranosyl ring; and group B™” signifies a pyrimidine base B5-a which is connected through the 1- nitrogen of formula . yr rR ~~ ar : A | Bsa zm" N wherein . R!®"” is hydrogen; RI is alkyl; YY” is O; 2 is O03 a hydrolyzable esters or ethers thereof and pharmaceutically acceptable salts thereof.
45. Compound as claimed in claim 44 which compound is 2’,3’-Dideoxy-5-ethyl-3’-methoxyuridine.
46. Compounds of formula I-f AMENDED SHEET
[ PCT/EP01/09653 oo HO a" ) id B» . [s isis b™” [grem I-f Rr" me wherein R12» is hydroxy; R27» is hydroxy; ) 5 N xX is (o}] } - : : a”, b>”, 7, d denoting asymmetric carbon atoms and forming a D- ribofuranosyl ring; and group B™”” signifies a pyrimidine base B5-b which is connected through the 1- nitrogen of formula Ye R1O™ RE
SN . PY | Bs z N : wherein : RIG» is hydrogen; R13» is halogen; Yr” is NR», Rl» is hydroxy; ddtides is Os hydrolyzable esters or ethers thereof and pharmaceutically acceptable selts thereof. CLEAN COPY
¢ PCT/EP01/09633
47. Compound as claimed in claim 46 which compound is '5-Fluoro-4-oximino- 1-(B-D-ribofuranosyl)pyrimidin-2(1H)-one.
48. Compounds of formula I-g HO am y Glildid Bm” [o isd lo id crm I-g R" “gz R® ) wherein Rl» is hydroxy; . ) R27» is hydroxy; Xp is 0; a’? pr, 7, 47 denoting asymmetric carbon atoms and forming a L- ribofuranosyl ring; and group B””’” signifies a pyrimidine base B5-c which is connected through the 1- nitrogen of formula ym CR RIE SN Pe | msc . VAdiaed N . wherein R029» is hydrogen; . } Rls is hydrogen; ] httdddd is NR», AMENDED SHEET
@® PCT/EP01/09633 RP is hydroxy; | : Zo is O; hydrolyzable esters or ethers thereof and pharmaceutically acceptable salts thereof.
49. Compound as claimed in claim 48 which compound is 4-Oximino-1-(B-L-ribofuranosyl)pyrimidin-2(1H)-one.
50. Compound of formula I as defined in claim 1 which compound is 6-(N-Methylpropylamino)-9-(p-D-ribofuranosyl)purine, 9-(B-D-Ribofuranosyl)-6-(4-thiomorpholinyl)purine, 6-(N-(2-Propenyl)methylamino)-9-(B-D-ribofuranosyl)purine, 6-(N-Methyl-2-propynylamino)-9-(B-D-ribofuranosyl) purine, : 6-[4-(4-Fluorophenyl)-1,2,5,6-tetrahydropyridyl]-9-(B-D-ribofuranosyl) purine, 6-[4-(2-Methoxyphenyl)piperazinyl]-9-(B-D-ribofuranosyl)purine, 6-(N-Methylphenylamino)-9-(B-D-ribofiranosyl)purine, 9-(B-D-Ribofuranosyl)-6-(1,2,4,5-6-(1-itetrahydro-3H-benzazepin-3-yl)purine, 5-(-D-ribofuranosyl)-6-(1,2,3,4-tetrahydro-2-isoquinclyl)purine, 9-(B-D-Ribofuranosyl)-6-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)purine, 6-[2-(4-Cyanomethylphenyl)ethylamino]-9-(B-D-ribofuranosyl)purine, 6-(2,3-Dihydro-1-indolyl)- 9-(B-D-ribofuranosyl)purine, AMENDED SHEET
( PCT/EP01/09633
9-(B-D-Ribofuranosyl)-6-(2,3,4,5-tetrahydro- 1,4-benzothiazepin-4-yl)purine, 9-(B-D-Ribofuranosyl)-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl)purine, 6-(8-Aminosulphonyl-2,3,4,5-tetrahydro-1H-2-benzazepin-2-yl)-9-(B-D- ribofuranosyl)purine, 6-(2-Isoindolinyl)-9-(B-D-ribofuranosyl)purine, 6-(7-Aminosulphonyi-2,3,4,5-tetrahydro- 1H-benzazepin-3-yl)-9-(B-D- : : ribofuranosyl)purine, 6-(10,1 1-Dihydro-5H-dibenzo]a,d] cyclohepten-5-jlamino)-9-(B-D- ribofuranosyl)purine, E 6-[N-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino}-9-(§-D- ribofuranosyl)purine, 6-[N-(5-Aminopentyl)methylamino]-9-(f-D-ribofuranosyl)purine, 6-Ethylmethylamino- 9-(B-D-ribofuranosyl)purine, 6-bis-{(3-Methyl)butylamino]-9-(B-D-ribofuranosyl)purine, 6-[2-Phenyl~(N-propionyl)ethylamino]-9-(B-D-ribofuranosyl purine, 6-(N-Benzoyl-2-phenylethylamino)-9-(B-D-ribofuranosyl)purine, ~ 1-Methyl-6-(2-phenylethylimino)-9-(B-D-ribofuranosyl)purine, 2-Amino-6-methylamino-$-(B-L-ribofuranosyl)purine, 6-[(N-Cyclohexyl)methylamino)-2- methylthio-9- (B-D-ribofiranasyl)purine, : 6-(1-Pyrrolyl)-9-(B-D-ribofuranosyl)purin-8-(7H)-one, 9-(3-Deoxy-B-D-ribofuranosyl)-6-(1-pyrrolyl) purine, CLEAN COPY
@ PCT/EP01/09633 6-(1-Pyrrolyl)-9-(B-L-ribofuranosyl)purine, oo 6~(1-Indolyl)-9-(B-D-ribofuranosyl)purine, 6~(1-Imidazolyl)-9-(B-D-ribofuranosyl)purine, 9-(B-D-Ribofuranosyl}-6-(1,2,4-triazol-1-yl)purine, 6-(1-Pyrazolyl)- 9-(B-D-ribofuranosyl)purine, ~ 6-(2-Phenylethylamino)- 9-(B-D-ribofuranosyl)purine-1-oxide, 8-(2-Phenylethylamino)adenosine, ’ $-(3-Phenylipropylamino)adenosine, 8-(4-Morpholinyl)adenosine, 8-(N-Methyl-2-phenylethylamino)adenosine,
&.(3-Pyridylmethylamino)adenosize, 8-(1,2,3,4-Tetrahydro-2-isoquinolyl)adenosine, . 8-[2-(4-Morpholinyl)ethylamino]adenasine, 8-(2-Cyclohexylethylamino)adenosine, 8-(2(R,S)-Phenylpropylamino)adenosine, 8-[2-(4-Methylphenyl) ethylamino]adenosine, ’ 8-[2-(1-methyl-2-pyrrolyl) ethylamino}adenosine, }
. 8-[2~(4-Aminosulphonylphenyl) ethylamino]adenosine, 8-(4-Phenyl-1-piperazinyl)adenosine, 8-(1-Naphthylmethylamino)adenosine, © 8-[2-(4-Hydroxyphenyl)ethylamino]adenosine, CLEAN COPY
() PCT/EP(Q1/09633 8-(4-Phenylbutylamino)adenosine, } * 8-]2-(4-Chlorophenyl)ethylamino)adenosine, 8-[2-(2,4-Dichlorophenyl)ethylamino)adenosine, 8-(2-Propenylamino)adenosine, 8-(1(R)-Methyl-2-phenylethylamino)adenosine, 8-(4-Fluorobenzylamino)adenosine, 8-[ (4-Hydroxycarbonyl)benzylamino] adenosine, 8-(2-propynylamino)adenosine, | : $-[(&-triffuoromethyi)benzylamino]adenosine, 8-[(2,5-Dimethoxy)benzylamino)adenosine, 8-[2-(2-Thienyl)ethylamino]adenosine, 8-[2-(4-Aminophenyl)ethylamino]adenosine, 8-(2-Phenoxyethylamino)adenosine, 8-[(2-Thienyl)methylamino)adenosine, :
15 . 8-[(4-tert-Butyl)benzylamino)adenosine, 8-(1(R)-Phenylethylamino)adenosine, 8-(1(S)-Phenylethylamino)adenosine, 8-(6-Phenylhexylemino)adenosine, 8-[2-Hydroxy-1(S)-phenyl)ethylamino]adenosine, '2'-Deoxy-8-(2-phenylethylamino)adenosine, 2’-Deoxy-8-(3-phenylpropylamino)adenosine, 8-Benzylamino-2’-deoxyadenosine, CLEAN COPY
® PCT/EP(}1/09633 2’-Deoxy-8-(4-phenylbutylamino)adenosine, * 2-Deoxy-8-(6-phenylhexylamino)adenosine, 8-Ethoxyadenosine, 9-(B-D-Ribofuranosyl)-6-(3-thienyl)purine, 9-(B-D-Ribofuranosyl)-6-(1-thianthrenyl)purine, 6-(4-Biphenylyl)-9-(B-D-ribofuranosyl) purine, 6-(4-Methylthiophenyl)-9-(B-D-ribofuranosyl) purine, 6-(9-Phenanthrenyl)-9-(B-D-ribofuranosyl)purine, 9-(B-D-Ribofuranosyl)-6-(3-trifluoromethylphenyl purine, 6-(2-Phenoxyphenyl)-9-(B-D-ribofuranosyl) purine, 6-(4-tert-Butylphenyl)-9-(B-D-ribofuranosyl) purine, 9-(B-D-Ribofuranosyl)-6-(2-triflucromethoxyphenyl)purine, 6-(4-Phenoxyphenyl)-9-(B-D-ribofuranosyl purine, 6~(2-Naphthyl)-9-(B-D-ribofuranosyl)purine,
6. (3-Biphenylyl)-9-(B-D-ribofuranosy)purine, 6-[4-(2-Methyipropyl)phenyl]-5-(B-D-ribofuranosyl)perine 6-(3-Fluorophenyl)-9-(B-D-ribofuranosyl)purine, : : 9-(§-D-Ribofuranosyl)-6- (&-triflnoromethyiphenyl)purine, - 6-(3-Ethoxyphenyl)-9-(B-D-ribofuranosyl)purine, 6—{3-(1-Methyl)ethylphenyl]-9-(B-D-ribofuranosyl)purize, CLEAN COPY
C PCT/EP01/09633 9-(B-D-Ribofuranosyl)-6-(4-trifluoromethoxyphenyl)purine, 6-(4-Ethylphenyl)-9-(B-D-ribofuranosyl)purine, 5-Fluoro-4-methylthio-1-(-D-ribofuranosyl) pyrimidin-2(1H)-one, © 5-Methyl-4-methylthio-1-(8-D-ribofuranosyl)pyrimidin-2(1H)-one, 2’,3’-Dideoxy-5-ethyl-3’-methoxyuridine, 4-(1-Pyrrolyl)-1-(B-D-ribofuranosyl)pyrimidin-2(1H)-one, 4-Oximino-1-(B-L-ribofuranosyl)pyrimidin-2(1H)-one, or 5-Fluoro-4-oximino-1-(B-D-ribofuranosyl)pyrimidin-2(1H)-one; hydrolyzable esters or ethers thereof and pharmaceutically acceptable salts thereof.
51. A compound, or hydrolysable ester, ether or pharmaceutically acceptable salt thereof, as claimed in any one of claims 35 to 50 for use in the treatment of a human or animal body.
52. A compound, or hydrolysable ester, ether or pharmaceutically acceptable salt thereof, as claimed in claim 51 for its use in the treatment of Hepatitis C Virus (HCV) infections.
53. Use of compounds, or hydrolysable ester, ether or pharmaceutically E acceptable salt thereof, as claimed in any one of claims 35 to 50 for the treatment of diseases mediated by the Hepatitis C Virus (HCV).
54. Use of compounds, or hydrolysable ester, ether or pharmaceutically acceptable salt thereof, as claimed in any one of claims 35 to 50 in the manufacture of a preparation for the treatment of diseases mediated by the Hepatitis C Virus HCV). : AMENDED SHEET
PCT/EP01/09633 @® - 224 -
55. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound, or hydrolysable ester, ether or pharmaceutically effective amount of a compound, or hydrolysable ester, ether or pharmaceutically acceptable salt thereof, as claimed in any one of claims 35 to 50 and, if desired, a pharmaceutically inert carrier, especially for use in the treatment of an Hepatitis C Virus (HCV) infection.
56. A process for preparing a medicament which process comprises bringing a compound, or hydrolysable ester, ether or pharmaceutically acceptable salt thereof, as claimed in any one of claims 35 to 50 into a galenical administration form together with a pharmaceutically inert carrier. i Co 57. Use of a compound, or hydrolysable ester, ether or pharmaceutically acceptable salt thereof, as claimed in any one of claims 35 to 50 in the manufacture of a preparation for the treatment of a human or animal body.
58. Use of compounds of formula I as defined in any one of claims 1 to 34, or a compound, or hydrolysable ester, ether or pharmaceutically acceptable salt thereof, as claimed in any one of claims 35 to 50, in the treatment of an Hepatitis C Virus (HCV) infection.
59. Use of a compound of formula I as defined in any one of claims 1 to 34, or a compound or hydrolysable ester, ether or pharmaceutically acceptable salt thereof, as claimed in any one of claims 35 to 50, in the manufacture of a preparation for the treatment of an Hepatitis C Virus (HCV) infection.
60. A substance or composition for use in a method for the treatrnent of diseases mediated by the Hepatitis C Virus (HCV), said substance or composition comprising a compound as defined in claim 1, and said method comprising administering said substance or composition.
61. A substance or composition for use in a method of treatment as claimed in : claim 60 wherein the integers are as defined in claim 3. AMENDED SHEET
PCT/EP01/09633 ® - 225 -
62. A substance or composition for use in a method of treatment as claimed in claims 60 or 61 wherein the integers are as defined in claim 4.
63. A substance or composition for use in a method of treatment as claimed in any one of claims 60 to 62 wherein the integers are as defined in claim 5.
64. A substance or composition for use in a method of treatment as claimed in any one of claims 60, 62 or 63 wherein the integers are as defined in claim 6.
65. A substance or composition for use in a method of treatment as claimed in any one of claims 60 or 62 to 64 wherein the integers are as defined in claim 7.
66. A substance or composition for use in a method of treatment as claimed in any one of claims 60 or 62 to 65 wherein the integers are as defined in claim 8.
67. A substance or composition for use in a method of treatment as claimed in claim 61 wherein the integers are as defined in claim 9.
68. A substance or composition for use in a method of treatment as claimed in any one of claims 61 or 67 wherein the integers are as defined in claim 10.
69. A substance or composition for use in a method of treatment as claimed in any one of claims 61, 67 or 68 wherein the integers are as defined in claim 11.
70. A substance or composition for use in a method of treatment as claimed in claim 60 which substance or composition is selected from the group as listed in claim 12.
71. A substance or composition for use in a method of treatment as claimed in any one of claims 60 to 63 wherein the integers are as defined in claim 13.
72. A substance or composition for use in a method of treatment as claimed in any one of claims 60 to 63 or 71 wherein the integers are as defined in claim 14. AMENDED SHEET
~ PCT/EP01/09633 @® - 226 -
73. A substance or composition for use in a method of treatment as claimed in any one of claims 60 to 63 or 71 which substance or composition is Adenosine-1-oxide, or 6-~(2-Phenylethylamino)-9-(8-D-ribofuranosyl)purine-1-oxide.
74. A substance or composition for use in a method of treatment as claimed in any one of claims 60 to 63 wherein the integers are as defined in claim 16.
75. A substance or composition for use in a method of treatment as claimed in any one of claims 60 to 63 or 74 wherein the integers are as defined in claim 17. : 76. A substance or composition for use in a method of treatment as claimed in claim 60 which substance or composition is selected from the group as listed in claim 18.
77. A substance or composition for use in a method of treatment as claimed in any one of claims 60, 62, or 63 wherein the integers are as defined in claim 19.
78. A substance or composition for use in a method of treatment as claimed in any one of claims 60, 62, 63 or 77 wherein the integers are as defined in claim 20.
79. A substance or composition for use in a method of treatment as claimed in any one of claims 60, 62, 63, 77 or 78 wherein the integers are as defined in claim
21.
80. A substance or composition for use in a method of treatment as claimed in claim 60 wherein the integers are as defined in claim 22.
81. A substance or composition for use in a method of treatment as claimed in any one of claims 60 or 80 wherein the integers are as defined in claim 23.
82. A substance or composition for use in a method of treatment as claimed in : claim 61 wherein the integers are as defined in claim 24. AMENDED SHEET
PCT/EP01/09633 ® -227 -
83. A substance or composition for use in a method of treatment as claimed in any one of claims 61 or 82 wherein the integers are as defined in claim 25.
84. A substance or composition for use in a method of treatment as claimed in any one of claims 61, 82 or 83 wherein the integers are as defined in claim 26. : 85. A substance or composition for use in a method of treatment as claimed in claim 60 which substance or composition is selected from the group as listed in claim 27.
86. A substance or composition for use in a method of treatment as claimed in claim 61 wherein the integers are as defined in claim 28. - 87. A substance or composition for use in a method of treatment as claimed in any one of claims 61 or 88 wherein the integers are as defined in claim 29.
88. A substance or composition for use in a method of treatment as claimed in any one of claims 60, 80, 81, 86 or 87 which substance or composition is selected from the group as listed in claim 30.
89. A substance or composition for use in a method of treatment as claimed in any one of claims 60, 62 or 63 wherein the integers are as defined in claim 31.
90. A substance or composition for use in a method of treatment as claimed in any one of claims 60 to 63 or 89 wherein the integers are as defined in claim 32.
91. A substance or composition for use in a method of treatment as claimed in claim 61 wherein the integers are as defined in claim 33.
82. A substance or composition for use in a method of treatment as claimed in claim 60 which substance or composition is selected from the group as listed in claim 34. AMENDED SHEET
: PCT/EP01/09633 9 -228 -
93. A substance or composition for use in a method for the treatment of a human or animal body, said substance or composition comprising a compound, or hydrolysable ester, ether or pharmaceutically acceptable salt thereof, as claimed in any one of claims 35 to 50, and said method comprising administering said substance or composition.
94. A substance or composition for use in a method for the treatment of diseases mediated by the Hepatitis C Virus (HCV), said substance or composition comprising a compound, or hydrolysable ester, ether or pharmaceutically acceptable salt thereof, as claimed in any one of claims 35 to 50, and said method comprising administering said substance or composition.
95. A substance or composition for use in a method of treating an Hepatitis C Virus (HCV) infection in a subject, said substance or composition comprising a compound of formula I as defined in any one of claims 1 to 34, or a compound, or hydrolysable ester, ether or pharmaceutically acceptable salt thereof, as claimed in any one of claims 35 to 50 and said method comprising administering a therapeutically effective amount of said substance or composition to said subject.
96. Use according to any of claims 1 or 2, or 53, or 54, or 57 to 59, substantially as herein described and illustrated.
97. A compound according to any of claims 35, or 37, or 39, or 41, or 44, or 46, or 48, substantially as herein described and illustrated.
98. A substance or composition for use in a method of treatment according to any of claims 51, or 55, or 60, or 93 to 95, substantially as herein described and } illustrated.
99. A process according to claim 56, substantially as herein described and illustrated.
100. The invention as hereinbefore described. AMENDED SHEET
PCI/EP01/09633 <P - 229 -
101. A new use of a compound of formula I as defined in claim 1, or 2 new use of a compound as claimed in any one of claims 35 to 50, or a hydrolysable ester, ether or pharmaceutically acceptable salt thereof, or a new use of a compound of formula I as defined in any one of claims 1 to 34; a new compound; a substance or composition for a new use in a method of treatment; or a new process for preparing a medicament, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0021285A GB0021285D0 (en) | 2000-08-30 | 2000-08-30 | Nucleoside derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200301540B true ZA200301540B (en) | 2004-06-21 |
Family
ID=9898525
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200301540A ZA200301540B (en) | 2000-08-30 | 2003-02-25 | Nucleoside derivatives for the treatment of Hepatitis C. |
Country Status (2)
Country | Link |
---|---|
GB (1) | GB0021285D0 (en) |
ZA (1) | ZA200301540B (en) |
-
2000
- 2000-08-30 GB GB0021285A patent/GB0021285D0/en not_active Ceased
-
2003
- 2003-02-25 ZA ZA200301540A patent/ZA200301540B/en unknown
Also Published As
Publication number | Publication date |
---|---|
GB0021285D0 (en) | 2000-10-18 |
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