EP1617848A2 - Phosphonat konjugate für die behandlung von krebs - Google Patents
Phosphonat konjugate für die behandlung von krebsInfo
- Publication number
- EP1617848A2 EP1617848A2 EP04750828A EP04750828A EP1617848A2 EP 1617848 A2 EP1617848 A2 EP 1617848A2 EP 04750828 A EP04750828 A EP 04750828A EP 04750828 A EP04750828 A EP 04750828A EP 1617848 A2 EP1617848 A2 EP 1617848A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- conjugate
- substituted
- formula
- alkyl
- independently
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 28
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 title claims description 68
- 150000001875 compounds Chemical class 0.000 claims abstract description 263
- 239000000203 mixture Substances 0.000 claims abstract description 89
- 238000000034 method Methods 0.000 claims abstract description 82
- -1 C^-methylguanine Chemical compound 0.000 claims description 295
- 229910052760 oxygen Inorganic materials 0.000 claims description 120
- 125000006239 protecting group Chemical group 0.000 claims description 113
- 125000004432 carbon atom Chemical group C* 0.000 claims description 97
- 125000000623 heterocyclic group Chemical group 0.000 claims description 90
- 229910052757 nitrogen Inorganic materials 0.000 claims description 82
- 229940002612 prodrug Drugs 0.000 claims description 67
- 239000000651 prodrug Chemical group 0.000 claims description 67
- 239000003814 drug Substances 0.000 claims description 65
- 206010028980 Neoplasm Diseases 0.000 claims description 60
- 229940079593 drug Drugs 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 56
- 229910052717 sulfur Inorganic materials 0.000 claims description 54
- 229940024606 amino acid Drugs 0.000 claims description 53
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- 150000001413 amino acids Chemical class 0.000 claims description 51
- 239000004480 active ingredient Substances 0.000 claims description 50
- 229910052740 iodine Inorganic materials 0.000 claims description 48
- 125000003342 alkenyl group Chemical group 0.000 claims description 47
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 47
- 125000000304 alkynyl group Chemical group 0.000 claims description 46
- 201000011510 cancer Diseases 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 45
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 45
- 229910052794 bromium Inorganic materials 0.000 claims description 42
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 42
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 41
- 150000002148 esters Chemical class 0.000 claims description 39
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 38
- 125000005647 linker group Chemical group 0.000 claims description 37
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 37
- 238000009472 formulation Methods 0.000 claims description 36
- 229910052799 carbon Inorganic materials 0.000 claims description 35
- 229920001184 polypeptide Polymers 0.000 claims description 35
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 34
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- PEHVGBZKEYRQSX-UHFFFAOYSA-N 7-deaza-adenine Chemical group NC1=NC=NC2=C1C=CN2 PEHVGBZKEYRQSX-UHFFFAOYSA-N 0.000 claims description 32
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical group NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 32
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical group O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 32
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 32
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 32
- 229910052731 fluorine Inorganic materials 0.000 claims description 30
- PZOUSPYUWWUPPK-UHFFFAOYSA-N 4-methyl-1h-indole Chemical compound CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 29
- 241000282414 Homo sapiens Species 0.000 claims description 29
- 239000003112 inhibitor Substances 0.000 claims description 29
- OIVLITBTBDPEFK-UHFFFAOYSA-N 5,6-dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 claims description 28
- LOSIULRWFAEMFL-UHFFFAOYSA-N 7-deazaguanine Chemical group O=C1NC(N)=NC2=C1CC=N2 LOSIULRWFAEMFL-UHFFFAOYSA-N 0.000 claims description 28
- 125000003282 alkyl amino group Chemical group 0.000 claims description 28
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 claims description 28
- DRAVOWXCEBXPTN-UHFFFAOYSA-N isoguanine Chemical compound NC1=NC(=O)NC2=C1NC=N2 DRAVOWXCEBXPTN-UHFFFAOYSA-N 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 239000012453 solvate Substances 0.000 claims description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 230000000694 effects Effects 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
- 230000003834 intracellular effect Effects 0.000 claims description 23
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 22
- 239000002207 metabolite Substances 0.000 claims description 22
- 125000003107 substituted aryl group Chemical group 0.000 claims description 21
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 238000001727 in vivo Methods 0.000 claims description 20
- 150000003852 triazoles Chemical class 0.000 claims description 20
- 229930024421 Adenine Natural products 0.000 claims description 18
- 229960000643 adenine Drugs 0.000 claims description 18
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 18
- 150000001356 alkyl thiols Chemical class 0.000 claims description 18
- 150000007942 carboxylates Chemical class 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 150000002596 lactones Chemical class 0.000 claims description 18
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 claims description 18
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 18
- 241001465754 Metazoa Species 0.000 claims description 17
- 150000001350 alkyl halides Chemical class 0.000 claims description 17
- 150000003951 lactams Chemical class 0.000 claims description 17
- 229940035893 uracil Drugs 0.000 claims description 17
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 claims description 16
- 125000002947 alkylene group Chemical group 0.000 claims description 16
- 229940104302 cytosine Drugs 0.000 claims description 16
- 229940113082 thymine Drugs 0.000 claims description 16
- 229960003087 tioguanine Drugs 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- 229910052721 tungsten Inorganic materials 0.000 claims description 16
- 150000008052 alkyl sulfonates Chemical class 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical class C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 claims description 14
- XQCZBXHVTFVIFE-UHFFFAOYSA-N 2-amino-4-hydroxypyrimidine Chemical compound NC1=NC=CC(O)=N1 XQCZBXHVTFVIFE-UHFFFAOYSA-N 0.000 claims description 14
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 claims description 14
- HCGYMSSYSAKGPK-UHFFFAOYSA-N 2-nitro-1h-indole Chemical compound C1=CC=C2NC([N+](=O)[O-])=CC2=C1 HCGYMSSYSAKGPK-UHFFFAOYSA-N 0.000 claims description 14
- FTBBGQKRYUTLMP-UHFFFAOYSA-N 2-nitro-1h-pyrrole Chemical compound [O-][N+](=O)C1=CC=CN1 FTBBGQKRYUTLMP-UHFFFAOYSA-N 0.000 claims description 14
- OVONXEQGWXGFJD-UHFFFAOYSA-N 4-sulfanylidene-1h-pyrimidin-2-one Chemical compound SC=1C=CNC(=O)N=1 OVONXEQGWXGFJD-UHFFFAOYSA-N 0.000 claims description 14
- NBAKTGXDIBVZOO-UHFFFAOYSA-N 5,6-dihydrothymine Chemical compound CC1CNC(=O)NC1=O NBAKTGXDIBVZOO-UHFFFAOYSA-N 0.000 claims description 14
- GSPMCUUYNASDHM-UHFFFAOYSA-N 5-methyl-4-sulfanylidene-1h-pyrimidin-2-one Chemical compound CC1=CNC(=O)N=C1S GSPMCUUYNASDHM-UHFFFAOYSA-N 0.000 claims description 14
- QNNARSZPGNJZIX-UHFFFAOYSA-N 6-amino-5-prop-1-ynyl-1h-pyrimidin-2-one Chemical compound CC#CC1=CNC(=O)N=C1N QNNARSZPGNJZIX-UHFFFAOYSA-N 0.000 claims description 14
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 claims description 14
- LHCPRYRLDOSKHK-UHFFFAOYSA-N 7-deaza-8-aza-adenine Chemical compound NC1=NC=NC2=C1C=NN2 LHCPRYRLDOSKHK-UHFFFAOYSA-N 0.000 claims description 14
- 229960005508 8-azaguanine Drugs 0.000 claims description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 14
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 claims description 14
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 claims description 14
- 229930010555 Inosine Natural products 0.000 claims description 14
- 241000124008 Mammalia Species 0.000 claims description 14
- MRWXACSTFXYYMV-UHFFFAOYSA-N Nebularine Natural products OC1C(O)C(CO)OC1N1C2=NC=NC=C2N=C1 MRWXACSTFXYYMV-UHFFFAOYSA-N 0.000 claims description 14
- 229930185560 Pseudouridine Natural products 0.000 claims description 14
- PTJWIQPHWPFNBW-UHFFFAOYSA-N Pseudouridine C Natural products OC1C(O)C(CO)OC1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-UHFFFAOYSA-N 0.000 claims description 14
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 14
- WGDUUQDYDIIBKT-UHFFFAOYSA-N beta-Pseudouridine Natural products OC1OC(CN2C=CC(=O)NC2=O)C(O)C1O WGDUUQDYDIIBKT-UHFFFAOYSA-N 0.000 claims description 14
- 229960003786 inosine Drugs 0.000 claims description 14
- MRWXACSTFXYYMV-FDDDBJFASA-N nebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC=C2N=C1 MRWXACSTFXYYMV-FDDDBJFASA-N 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- PTJWIQPHWPFNBW-GBNDHIKLSA-N pseudouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-GBNDHIKLSA-N 0.000 claims description 14
- HBCQSNAFLVXVAY-UHFFFAOYSA-N pyrimidine-2-thiol Chemical compound SC1=NC=CC=N1 HBCQSNAFLVXVAY-UHFFFAOYSA-N 0.000 claims description 14
- 125000004450 alkenylene group Chemical group 0.000 claims description 13
- 125000004419 alkynylene group Chemical group 0.000 claims description 13
- 230000002401 inhibitory effect Effects 0.000 claims description 13
- 125000005360 alkyl sulfoxide group Chemical group 0.000 claims description 12
- 125000005362 aryl sulfone group Chemical group 0.000 claims description 12
- 125000005361 aryl sulfoxide group Chemical group 0.000 claims description 12
- 125000005110 aryl thio group Chemical group 0.000 claims description 12
- 125000002837 carbocyclic group Chemical group 0.000 claims description 12
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 12
- 150000002825 nitriles Chemical class 0.000 claims description 12
- 150000003254 radicals Chemical class 0.000 claims description 12
- 229940124530 sulfonamide Drugs 0.000 claims description 12
- 150000003456 sulfonamides Chemical class 0.000 claims description 12
- 125000005208 trialkylammonium group Chemical group 0.000 claims description 12
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 125000003368 amide group Chemical group 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 229910019142 PO4 Inorganic materials 0.000 claims description 9
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims description 9
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 8
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 8
- 238000000338 in vitro Methods 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical group [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
- 239000010452 phosphate Chemical group 0.000 claims description 8
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 7
- 150000005215 alkyl ethers Chemical class 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 210000000214 mouth Anatomy 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 210000003491 skin Anatomy 0.000 claims description 7
- 150000003459 sulfonic acid esters Chemical class 0.000 claims description 7
- 229960004441 tyrosine Drugs 0.000 claims description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 6
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 6
- 150000008378 aryl ethers Chemical class 0.000 claims description 6
- 210000004556 brain Anatomy 0.000 claims description 6
- 150000003857 carboxamides Chemical class 0.000 claims description 6
- 210000004072 lung Anatomy 0.000 claims description 6
- 239000002777 nucleoside Substances 0.000 claims description 6
- 125000004950 trifluoroalkyl group Chemical group 0.000 claims description 6
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 5
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 5
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 5
- 239000004473 Threonine Substances 0.000 claims description 5
- 210000001185 bone marrow Anatomy 0.000 claims description 5
- 210000000481 breast Anatomy 0.000 claims description 5
- 210000001072 colon Anatomy 0.000 claims description 5
- 150000002430 hydrocarbons Chemical group 0.000 claims description 5
- 210000004185 liver Anatomy 0.000 claims description 5
- 125000004437 phosphorous atom Chemical group 0.000 claims description 5
- 229960002898 threonine Drugs 0.000 claims description 5
- 210000001685 thyroid gland Anatomy 0.000 claims description 5
- 230000004614 tumor growth Effects 0.000 claims description 5
- 229960005261 aspartic acid Drugs 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229960002885 histidine Drugs 0.000 claims description 4
- HPZMWTNATZPBIH-UHFFFAOYSA-N 1-methyladenine Chemical compound CN1C=NC2=NC=NC2=C1N HPZMWTNATZPBIH-UHFFFAOYSA-N 0.000 claims description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 3
- 238000013160 medical therapy Methods 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 3
- ALBODLTZUXKBGZ-JUUVMNCLSA-N (2s)-2-amino-3-phenylpropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 ALBODLTZUXKBGZ-JUUVMNCLSA-N 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 101710200424 Inosine-5'-monophosphate dehydrogenase Proteins 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 2
- 230000000340 anti-metabolite Effects 0.000 claims description 2
- 229940100197 antimetabolite Drugs 0.000 claims description 2
- 239000002256 antimetabolite Substances 0.000 claims description 2
- 239000003443 antiviral agent Substances 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 229920000729 poly(L-lysine) polymer Polymers 0.000 claims description 2
- 229920002643 polyglutamic acid Polymers 0.000 claims description 2
- 108010050934 polyleucine Proteins 0.000 claims description 2
- 108010055896 polyornithine Proteins 0.000 claims description 2
- 108010000222 polyserine Proteins 0.000 claims description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims 4
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 claims 4
- 210000000436 anus Anatomy 0.000 claims 4
- 210000000988 bone and bone Anatomy 0.000 claims 4
- 208000035269 cancer or benign tumor Diseases 0.000 claims 4
- 210000000748 cardiovascular system Anatomy 0.000 claims 4
- 210000003169 central nervous system Anatomy 0.000 claims 4
- 210000003679 cervix uteri Anatomy 0.000 claims 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims 4
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 claims 4
- 210000003238 esophagus Anatomy 0.000 claims 4
- 210000001508 eye Anatomy 0.000 claims 4
- 201000009277 hairy cell leukemia Diseases 0.000 claims 4
- 210000003128 head Anatomy 0.000 claims 4
- 210000003026 hypopharynx Anatomy 0.000 claims 4
- 210000003734 kidney Anatomy 0.000 claims 4
- 210000000867 larynx Anatomy 0.000 claims 4
- 210000001165 lymph node Anatomy 0.000 claims 4
- 210000002346 musculoskeletal system Anatomy 0.000 claims 4
- 201000005962 mycosis fungoides Diseases 0.000 claims 4
- 210000001989 nasopharynx Anatomy 0.000 claims 4
- 210000003739 neck Anatomy 0.000 claims 4
- 230000001613 neoplastic effect Effects 0.000 claims 4
- 210000005036 nerve Anatomy 0.000 claims 4
- 210000003300 oropharynx Anatomy 0.000 claims 4
- 210000001672 ovary Anatomy 0.000 claims 4
- 210000000496 pancreas Anatomy 0.000 claims 4
- 210000001428 peripheral nervous system Anatomy 0.000 claims 4
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 claims 4
- 210000002307 prostate Anatomy 0.000 claims 4
- 210000000664 rectum Anatomy 0.000 claims 4
- 210000001525 retina Anatomy 0.000 claims 4
- 210000003079 salivary gland Anatomy 0.000 claims 4
- 210000002027 skeletal muscle Anatomy 0.000 claims 4
- 210000002460 smooth muscle Anatomy 0.000 claims 4
- 210000004872 soft tissue Anatomy 0.000 claims 4
- 210000000278 spinal cord Anatomy 0.000 claims 4
- 210000002784 stomach Anatomy 0.000 claims 4
- 210000001550 testis Anatomy 0.000 claims 4
- 210000002105 tongue Anatomy 0.000 claims 4
- 210000000626 ureter Anatomy 0.000 claims 4
- 210000003932 urinary bladder Anatomy 0.000 claims 4
- 210000002229 urogenital system Anatomy 0.000 claims 4
- CKOMXBHMKXXTNW-UHFFFAOYSA-N 6-methyladenine Chemical compound CNC1=NC=NC2=C1N=CN2 CKOMXBHMKXXTNW-UHFFFAOYSA-N 0.000 claims 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims 1
- 230000002924 anti-infective effect Effects 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 125000002993 cycloalkylene group Chemical group 0.000 claims 1
- 208000030159 metabolic disease Diseases 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 16
- 230000008569 process Effects 0.000 abstract description 12
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 3
- 239000011574 phosphorus Substances 0.000 abstract description 3
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 235000001014 amino acid Nutrition 0.000 description 49
- 210000004027 cell Anatomy 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 31
- 230000022131 cell cycle Effects 0.000 description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
- 239000002253 acid Substances 0.000 description 23
- 230000018199 S phase Effects 0.000 description 20
- 239000000126 substance Substances 0.000 description 18
- 230000002378 acidificating effect Effects 0.000 description 17
- 238000003776 cleavage reaction Methods 0.000 description 17
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- 229960000641 zorubicin Drugs 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- ZAYJDMWJYCTABM-WHFBIAKZSA-N β-hydroxyleucine Chemical compound CC(C)[C@H](O)[C@H](N)C(O)=O ZAYJDMWJYCTABM-WHFBIAKZSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
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- C07D239/72—Quinazolines; Hydrogenated quinazolines
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
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- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
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- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
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- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
- C07F9/655354—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Definitions
- the invention relates generally to compounds with anti-cancer activity.
- agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable. This may result in adverse drug side effects, and often limits the dose of a drug (e.g., glucocorticoids and other anti-inflammatory drugs) that can be administered.
- a drug e.g., glucocorticoids and other anti-inflammatory drugs
- oral administration can result in either (a) uptake of the drug through the cellular and tissue barriers, e.g., blood/brain, epithelial, cell membrane, resulting in undesirable systemic distribution, or (b) temporary residence of the drug within the gastrointestinal tract. Accordingly, a major goal has been to develop methods for specifically targeting agents to cells and tissues.
- Benefits of such treatment includes avoiding the general physiological effects of inappropriate delivery of such agents to other cells and tissues, such as uninfected cells.
- Intracellular targeting may be achieved by methods and compositions which allow accumulation or retention of biologically active agents inside cells.
- Many of the current treatment regimes for cell proliferation diseases such as psoriasis and cancer utilize compounds which inhibit DNA synthesis. Such compounds are toxic to cells generally but their toxic effect on rapidly dividing cells such as tumor cells can be beneficial.
- Alternative approaches to anti- proliferative agents which act by mechanisms other than the inhibition of DNA synthesis have the potential to display enhanced selectivity of action.
- Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication. They are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation.
- EGF epidermal growth factor
- Various classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research, 1993, 60, 43- 73) based on families of growth factors which bind to different receptor tyrosine kinases.
- the classification includes Class I receptor tyrosine kinases comprising the EGF family of receptor tyrosine kinases such as the EGF, TGF.alpha., NEU, erbB, Xmrk, HER and let23 receptors, Class II receptor tyrosine kinases comprising the insulin family of receptor tyrosine kinases such as the insulin, IGFI and insulin-related receptor (IRR) receptors and Class III receptor tyrosine kinases comprising the platelet-derived growth factor (PDGF) family of receptor tyrosine kinases such as the PDGF. alpha., PDGF.beta. and colony-stimulating factor 1 (CSF1) receptors.
- EGF EGF family of receptor tyrosine kinases
- TGF.alpha. such as the EGF, TGF.alpha., NEU, erbB, Xmrk, HER and let23 receptors
- Class I kinases such as the EGF family of receptor tyrosine kinases are frequently present in common human cancers such as breast cancer (Sainsbury et. al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21 and Klijn et al., Breast Cancer Res. Treat., 1994, 29, 73), non-small cell lung cancers (NSCLCs) including adenocarcinomas (Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi et al., Int. J.
- NSCLCs non-small cell lung cancers
- EGF receptors which possess tyrosine kinase activity are overexpressed in many human cancers such as brain, lung squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynaecological and thyroid tumors. Accordingly it has been recognized that an inhibitor of receptor tyrosine kinases should be of value as a selective inhibitor of the growth of mammalian cancer cells (Yaish et al. Science, 1988, 242, 933).
- Inhibitors of tumor growth are useful to limit the establishment and progression of cancer, as well as in diagnostic assays for cancer.
- anti-cancer therapeutic agents i.e. drugs, having improved anti-cancer, as well as pharmacokinetic properties, including enhanced activity against development of cancer, improved oral bioavailability, greater potency and extended effective half-life in vivo.
- anti-cancer compounds should be active against various cancers, have distinct resistance profiles, fewer side effects, less complicated dosing schedules, and orally active.
- a less onerous dosage regimen such as one pill, once per day.
- Intracellular targeting may be achieved by methods and compositions that allow accumulation or retention of biologically active agents inside cells.
- the present invention provides novel analogs of anti-cancer compounds. Such novel anti-cancer compound analogs possess all the utilities of anti-cancer compounds and optionally provide cellular accumulation as set forth below.
- the present invention provides compositions and methods for treatingcancer or therapeutic activity against cancer.
- the present invention relates generally to the accumulation or retention of therapeutic compounds inside cells.
- the invention is more particularly related to attaining high concentrations of phosphonate-containing molecules in cancer cells. Such effective targeting may be applicable to a variety of therapeutic formulations and procedures.
- the invention provides a compound of the invention which is a conjugate comprising a chemotherapeutic agent linked to one or more phosphonate groups.
- the invention provides a compound of any one of formulae 500-601:
- a 0 is A 1 , A 2 or W 3 with the proviso that the conjugate includes at least one A
- A' is:
- a 2 is:
- a 3 is:
- Y 1 is independently O, S, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R X )( R x ));
- Y2 z is independently a bond, O, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ),
- R x is independently H, R 1 , R 2 , W 3 , a protecting group, or the formula:
- R y is independently H, W 3 , n R2 or a protecting group
- R , 1 i s independently H or alkyl of 1 to 18 carbon atoms
- R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups
- R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a torn, then R 3 is R 3c or R 3d ;
- R 3a is F, CI, Br, I, -CN, N 3 or -NO 2 ;
- R 3b is Y'
- R 3c is -R x , -N(R X )(R X ), -SR X , -S(O)R x , -S(O) 2 R x , -S(O)(OR x ), -
- R 3d is -C(Y')R X , -C(Y')OR x or -C(Y')(N(R X )(R X ));
- R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
- R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
- W 3 is W 4 or W 5 ;
- W 4 is R 5 , -C(Y')R 5 , -C(Y')W 5 , -SO M2 R 5 , or -SO M2 W 5 ;
- W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
- W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups
- M2 is 0, 1 or 2;
- M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12
- M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- Mia, Ml c, and Mid are independently 0 or 1 ;
- M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12
- the invention provides a compound of the formula:
- DRUG is a compound of any one of formulae 500-601; nn is 1, 2, or 3; A 0 is A 1 , A 2 or W 3 with the proviso that the conjugate includes at least one A
- a 1 is:
- a 2 is:
- a 3 is:
- Y 1 is independently O, S, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR ), or N(N(R X )( R x ));
- Y 2 is independently a bond, O, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R X )( R x )), -S(O)M2-, or -S(O) M2 -S(O) M2 -; and when Y 2 joins two phosphorous atoms Y 2 can also be C(R 2 )(R 2 );
- R x is independently H, R 1 , R 2 , W 3 , a protecting group, or the formula:
- R y is independently H, W 3 , R 2 or a protecting group;
- R 1 is independently H or alkyl of 1 to 18 carbon atoms;
- R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3
- R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
- R 3a is F, CI, Br, I, -CN, N 3 or -NO 2 ;
- R 3b is Y'
- R 3c is -R x , -N(R X )(R X ), -SR X , -S(O)R x , -S(O) 2 R x , -S(O)(OR x ), -
- R 3d is -C(Y')R X , -C(Y')OR x or -C(Y')(N(R X )(R X ));
- R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
- R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups; W 3 is W 4 or W 5 ;
- W 4 is R 5 , -C(Y')R 5 , -C(Y')W 5 , -SO M2 R 5 , or -SO M2 W 5 ;
- W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
- W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups; M2 is 0, 1 or 2;
- M12a is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12
- M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- Mia, Ml c, and Mid are independently 0 or 1 ; and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12.
- the invention provides a compound of any one of formulae 1-336:
- a 0 is A 1 ;
- a 1 is:
- a 3 is:
- Y 1 is independently O, S, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R X )( R x ));
- Y 2 is independently a bond, O, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), N( (R X )( R x )), -S(O)M2-, or -S(O) M2 -S(O) M 2-; and when Y 2 joins two
- 9 9 9 9 phosphorous atoms Y can also be C(R )(R );
- R x is independently H, R 2 , W 3 , a protecting group, or the formula:
- R y is independently H, W 3 , R 2 or a protecting group;
- R 1 is independently H or alkyl of 1 to 18 carbon atoms;
- R 2 is independently H, R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups;
- R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R d ;
- R 3a is F, CI, Br, I, -CN, N 3 or -NO 2 ;
- R 3b is Y»;
- R 3c is -R x , -N(R X )(R X ), -SR X , -S(O)R x , -S(O) 2 R x , -S(O)(OR x ), - S(O) 2 (OR x ), -OC(Y')R x , -OC(Y')OR x , -OC(Y')(N(R x )(R x )), -SC(Y')R X , - SC(Y')OR x , -SC(Y')(N(R X )(R X )), -N(R X )C(Y')R X , -N(R x )C(Y')OR x , or - N(R X )C(Y')(N(R X )(R X )) ;
- R 3d is -C(Y')R X , -C(Y')OR x or -C(Y')( (R x )(R x ));
- R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
- R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
- R 5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 3 groups;
- W 3 is W 4 or W 5 ;
- W 4 is R 5 , -C(Y')R 5 , -C(Y')W 5 , -SO 2 R 5 , or -SO 2 W 5 ;
- W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
- W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups
- M2 is 0, 1 or 2;
- M12a is l , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- Mia, Ml c, and Mid are independently 0 or 1 ;
- M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- X 50 is H F, or CI; and X 5l is H or Cl.
- the invention provides a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
- This invention provides a method of increasing cellular accumulation and retention of drug compounds, thus improving their therapeutic and diagnostic value, comprising linking the compound to one or more (e.g., 1, 2, 3, or 4) phosphonate groups.
- This invention also pertains to a method of increasing cellular accumulation and retention of a chemotherapeutic agent comprising linking the compound to one or more phosphonate groups.
- the invention also provides a method of treating cancer in a mammal, comprising administering a compound of the invention to the mammal.
- the invention also provides a compound of the invention for use in medical therapy preferably for use in treating cancer, as well as the use of a compound of the invention for the manufacture of a medicament useful for the treatment of cancer.
- the invention also provides a method for inhibiting cancer activity comprising contacting a sample in need of such treatment with a compound or composition of the invention.
- the invention also provides processes and novel intermediates disclosed herein which are useful for preparing compounds of the invention. Some of the compounds of the invention are useful to prepare other compounds of the invention. The invention also provides novel methods for syntheses of the compounds of the invention.
- Bioavailability is the degree to which the pharmaceutically active agent becomes available to the target tissue after the agent's introduction into the body. Enhancement of the bioavailability of a pharmaceutically active agent can provide a more efficient and effective treatment for patients because, for a given dose, more of the pharmaceutically active agent will be available at the targeted tissue sites.
- phosphonate and “phosphonate group” include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to a heteroatom , 3) single-bonded to a heteroatom, and 4) single-bonded to another heteroatom, wherein each heteroatom can be the same or different.
- phosphonate and “phosphonate group” also include functional groups or moieties that comprise a phosphorous in the same oxidation state as the phosphorous described above, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having the characteriatics described above.
- the terms “phosphonate” and “phosphonate group” include phosphonic acid, phosphonic monoester, phosphonic diester, phosphonamidate, and phosphonthioate functional groups.
- the terms “phosphonate” and “phosphonate group” include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double- bonded to an oxygen, 3) single-bonded to an oxygen, and 4) single-bonded to another oxygen, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having such characteriatics.
- the terms "phosphonate” and “phosphonate group” include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to an oxygen, 3) single-bonded to an oxygen or nitrogen, and 4) single-bonded to another oxygen or nitrogen, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having such characteriatics.
- prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s).
- a prodrug is thus a covalently modified analog or latent form of a therapeutically- active compound.
- Prodrug moiety refers to a labile functional group which separates from the active anti-cancer compound compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, "Design and Application of Prodrugs” in A Textbook of Drug Design and Development (1991 . P.
- Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases.
- Prodrug moieties can serve to enhance solubility, abso ⁇ tion and lipophilicity to optimize drug delivery, bioavailability and efficacy.
- a prodrug moiety may include an active metabolite or drug itself.
- the acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72: 324; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756.
- acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability.
- a close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention.
- the phosphonate group may be a phosphonate prodrug moiety.
- the prodrug moiety may be sensitive to hydrolysis, such as, but not limited to a pivaloyloxymethyl carbonate (POC) or POM group.
- the prodrug moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate ester or a phosphonamidate-ester group.
- Aryl esters of phosphorus groups are reported to enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109- 41 15). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ⁇ rt/70-or/r ⁇ ra-position may accelerate the hydrolysis.
- Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g., esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-O bond to generate the phosphoric acid and the quinone methide intermediate.
- enzymes e.g., esterases, oxidases, etc.
- this class of prodrugs are described by Mitchell et al. (1992) J. Chem. Soc. Perkin Trans. 7/ 2345; Glazier WO 91/19721.
- Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier WO 91/19721).
- Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs.
- These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Deesterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria et al. (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (Erion et al., US Patent No. 6312662).
- Protecting group refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole.
- Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion.
- Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools.
- Chemically protected intermediates may themselves be biologically active or inactive.
- Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs.
- Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug.
- Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g., alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
- any reference to any of the compounds of the invention also includes a reference to a physiologically acceptable salt thereof.
- physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 + (wherein X is C ⁇ -C alkyl).
- Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
- Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX + (wherein X is independently selected from H or a C ⁇ -C alkyl group).
- salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
- salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
- Alkyl is C ]-Ci 8 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1- propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (j-Pr, i-propyl, -CH(CH3)2), 1- butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l -propyl (i-Bu, i-butyl, - CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2- propyl (t-Bu, t-butyl, -C(CH3)3), 1 -pentyl (n-pentyl, -CH2CH2CH2CH3)), 1 -
- Alkynyl is C2-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to, acetylenic (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH),
- Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
- Typical alkylene radicals include, but are not limited to, methylene (-CH 2 -) 1,2-ethyl (-CH 2 CH 2 -), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
- Alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
- Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
- Typical alkynylene radicals include, but are not limited to, acetylene (-C ⁇ C-), propargyl (-CH 2 C ⁇ C-), and 4-pentynyl (-CH 2 CH 2 CH 2 C ⁇ CH-).
- Aryl means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
- Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.
- “Arylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
- Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, , naphthylmethyl, 2-naphthylethan-l- yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like.
- the arylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
- Substituted alkyl mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.
- Heterocycle as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.
- “heterocycle” includes a "carbocycle” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S).
- heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl
- carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
- carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5- pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3- pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
- nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, IH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
- nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1 -pyrrolyl, 1 -imidazolyl, 1- pyrazolyl, and 1 -piperidinyl.
- Carbocycle refers to a saturated, unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
- Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
- Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
- Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1- cyclopent-1-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-1-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
- Linker or “link” refers to a chemical moiety comprising a covalent bond or a chain or group of atoms that covalently attaches a phosphonate group to a drug.
- Linkers include portions of substituents A and A , which include moieties such as: repeating units of alkyloxy (e.g., polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
- moieties such as: repeating units of alkyloxy (e.g., polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
- chiral refers to molecules which have the property of non- superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
- stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
- Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
- Enantiomers refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
- treatment or “treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
- Stereochemical definitions and conventions used herein generally follow
- d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
- a compound prefixed with (+) or d is dextrorotatory.
- these stereoisomers are identical except that they are mirror images of one another.
- a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
- a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
- racemic mixture and racemate refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
- protecting groups include prodrug moieties and chemical protecting groups.
- Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group "PG" will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. The PG groups do not need to be, and generally are not, the same if the compound is substituted with multiple PG. In general, PG will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency.
- the order of deprotection to yield free, deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.
- Various functional groups of the compounds of the invention may be protection.
- protecting groups for -OH groups are claims of "ether- or ester-forming groups”.
- Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein.
- some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.
- protecting groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for acids see Greene as set forth below.
- Such groups include by way of example and not limitation, esters, amides, hydrazides, and the like.
- Ester-forming groups include: (1) phosphonate ester-forming groups, such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3) sulphur ester-forming groups, such as sulphonate, sulfate, and sulfinate.
- phosphonate ester-forming groups such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphon-bis-amidates
- carboxyl ester-forming groups such as sulphonate, sulfate, and sulfinate.
- the phosphonate moieties of the compounds of the invention may or may not be prodrug moieties, i.e. they may or may be susceptible to hydrolytic or enzymatic cleavage or modification. Certain phosphonate moieties are stable under most or nearly all metabolic conditions. For example, a dialkylphosphonate, where the alkyl groups are two or more carbons, may have appreciable stability in vivo due to a slow rate of hydrolysis.
- phosphonate prodrug moieties a large number of structurally-diverse prodrugs have been described for phosphonic acids (Freeman and Ross in Progress in Medicinal Chemistry 34: 1 12- 147 ( 1997) and are included within the scope of the present invention.
- An exemplary phosphonate ester-forming group is the phenyl carbocycle in substructure A having the formula:
- may be H or C 1 - 2 alkyl; ml is 1, 2, 3, 4, 5, 6, 7 or 8, and the phenyl carbocycle is substituted with 0 to 3 R 2 groups.
- Yi is O, a lactate ester is formed, and where is N(R 2 ), N(OR 2 ) or N(N(R 2 ) 2 , a phosphonamidate ester results.
- a protecting group typically is bound to any acidic group such as, by way of example and not limitation, a -CO2H or -C(S)OH group, thereby resulting in -CO2R x where R x is defined herein.
- R for example includes the enumerated ester groups of WO 95/07920. Examples of protecting groups include:
- aromatic groups optionally are polycyclic or monocyclic. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4- pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5-pyrimidinyl,
- Such groups include 2-, 3- and 4-alkoxyphenyl (C1-C12 alkyl), 2-, 3- and 4- methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4- hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6- hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2-, 3- and 4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (including 2-, 3- and 4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-,
- esters of 2-carboxyphenyl and C1-C4 alkylene-C3-C 6 aryl (including benzyl, - CH2-pyrrolyl, -CH2-thienyl, -CH2-imidazolyl, -CH2-oxazolyl, -CH2-isoxazolyl, -CH2-thiazolyl, -CH2-isothiazolyl, -CH2-pyrazolyl, -CH2-pyridinyl and -CH2- pyrimidinyl) substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, C1-C12 alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C1-C12 haloalkyl (1 to 6 halogen atoms; including - CH2CCI3), C1-C12 alkyl (including methyl and ethyl), C 2 -C ⁇ 2 al
- hydroxyl groups of the compounds of this invention optionally are substituted with one of groups III, IV or V disclosed in WO 94/21604, or with isopropyl.
- Table A lists examples of protecting group ester moieties that for example can be bonded via oxygen to -C(O)O- and -P(O)(O-)2 groups.
- amidates also are shown, which are bound directly to -C(O)- or -P(O)2- Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting the compound herein having a free hydroxyl with the corresponding halide (chloride or acyl chloride and the like) and N ,N-dicyclohexyl-N-morpholine carboxamidine (or another base such as DBU, triethylamine, CsCO 3 , N,N-dimethylaniIine and the like) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone).
- the esters of structures 5-7, 11, 12, 21, and 23-26 are synthesized by reaction of the alcohol or alkoxide salt (or the corresponding amines in the case of compounds such as 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate (or another activated phosphonate).
- # - chiral center is (R), (S) or racemate.
- esters that are suitable for use herein are described in EP 632048.
- Protecting groups also includes "double ester" forming profunctionalities
- alkyl- or aryl-acyloxyalkyl groups of the structure -CH(R' or W 5 )O((CO)R 37 ) or -CH(R' or W 5 )((CO)OR 38 ) (linked to oxygen of the acidic group) wherein R 37 and R 38 are alkyl, aryl, or alkylaryl groups (see U.S. Patent No. 4968788).
- R 37 and R 38 are bulky groups such as branched alkyl, ortho- substituted aryl, meta-substituted aryl, or combinations thereof, including normal, secondary, iso- and tertiary alkyls of 1-6 carbon atoms.
- An example is the pivaloyloxymethyl group.
- Such useful protecting groups are alkylacyloxymethyl esters and their derivatives, including -
- the protected acidic group is an ester of the acidic group and is the residue of a hydroxyl-containing functionality.
- an amino compound is used to protect the acid functionality.
- the residues of suitable hydroxyl or amino-containing functionalities are set forth above or are found in WO 95/07920.
- Of particular interest are the residues of amino acids, amino acid esters, polypeptides, or aryl alcohols. Typical amino acid, polypeptide and carboxyl-esterified amino acid residues are described on pages 11-18 and related text of WO 95/07920 as groups LI or L2.
- WO 95/07920 expressly teaches the amidates of phosphonic acids, but it will be understood that such amidates are formed with any of the acid groups set forth herein and the amino acid residues set forth in WO 95/07920.
- Typical esters for protecting acidic functionalities are also described in WO 95/07920, again understanding that the same esters can be formed with the acidic groups herein as with the phosphonate of the '920 publication.
- Typical ester groups are defined at least on WO 95/07920 pages 89-93 (under R ⁇ 1 or
- esters of unsubstituted aryl such as phenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy- and/or alkylestercarboxy-substituted aryl or alkylaryl, especially phenyl, ortho-ethoxyphenyl, or C 1 -C 4 alkylestercarboxyphenyl (salicylate C ⁇ -C ⁇ 2 alkylesters).
- the protected acidic groups are useful as prodrugs for oral administration. However, it is not essential that the acidic group be protected in order for the compounds of this invention to be effectively administered by the oral route.
- the compounds of the invention having protected groups in particular amino acid amidates or substituted and unsubstituted aryl esters are administered systemically or orally they are capable of hydrolytic cleavage in vivo to yield the free acid.
- One or more of the acidic hydroxyls are protected. If more than one acidic hydroxyl is protected then the same or a different protecting group is employed, e.g., the esters may be different or the same, or a mixed amidate and ester may be used.
- Typical hydroxy protecting groups described in Greene include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters, and carbonates.
- substituted methyl and alkyl ethers include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters, and carbonates.
- Methyl Ethers (Methoxymethyl, Methylthiomethyl, t- Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p- Methoxy benzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t-
- Ethyl Ethers 1 -Ethoxyethyl, 1 -(2-Chloroethoxy)ethyl, 1 -Methyl- 1 -methoxyethyl, 1 -Methyl- 1 -benzyloxyethy 1, 1 -Methyl- 1 -benzy loxy-2- fluoroethyl, 2,2,2-Trichloroethyl, 2-Trimethylsilylethyl, 2-
- Typical 1 ,2-diol protecting groups are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1- t-Butylethylidene, 1-Phenylethylidene, (4-Methoxyphenyl)ethylidene, 2,2,2- Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentyl idene, Cyclohexylidene, Cycloheptylidene, Benzylidene,/?-Methoxybenzylidene, 2,4- Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2- ⁇ itrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1- Methoxyethylidene, 1
- Tetraisopropyldisiloxanylidene and Tetra-t-butoxydisiloxane-l,3-diylidene
- Cyclic Carbonates Cyclic Boronates, Ethyl Boronate and Phenyl Boronate.
- 1,2-diol protecting groups include those shown in Table B, still more typically, epoxides, acetonides, cyclic ketals and aryl acetals.
- R ⁇ is C ⁇ -C6 alkyl
- Another set of protecting groups include any of the typical amino protecting groups described by Greene at pages 315-385. They include:
- Ethyl (2,2,2-trichoroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1 -( 1 -adamantyl)- 1 -methylethyl, 1 , 1 -dimethyl-2-haloethyl, 1 , 1 -dimethyl-2,2- dibromoethyl, l,l-dimethyl-2,2,2-trichloroethyl, 1 -methyl- 1 -(4- biphenylyl)ethyl, l-(3,5-di-t-butylphenyl)-l -methylethyl, 2-(2'- and 4'- pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl
- N-Alkyl and N-Aryl Amines (N-methyl, N-allyl, N-[2- (trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-(l-isopropyl-4-nitro-2- oxo-3-pyrrolin-3-yl), Quaternary Ammonium Salts, N-benzyl, N-di(4- methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4- methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9- fluorenylmethylene, N-ferrocenylmethyl, N-2-picolylamine N-oxide); • Imine Derivatives: (N-l,l-dimethylthiomethylene, N-benzylidene, N-p- methoxybenyl idene, N-dipheny
- N-Metal Derivatives N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, N- copper or N-zinc chelate;
- N-benzenesulfenyl N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N- pentachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulfenyl, N- triphenylmethylsulfenyl, N-3-nitropyridinesulfenyl
- N-sulfonyl Derivatives N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4- methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6- dimethyl-4-methoxybenzenesulfonyl, N-p
- Another protecting group, also useful as a prodrug for amino or -NH(R 5 ), is:
- amino acid and polypeptide protecting group and conjugates An amino acid or polypeptide protecting group of a compound of the invention has the structure R l5 NHCH(R l6 )C(O)-, where R 15 is H, an amino acid or polypeptide residue, or R 5 , and R 16 is defined below.
- R 16 is lower alkyl or lower alkyl (Cj-C ⁇ ) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C 6 -C aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate.
- R 10 is generally the side group of a naturally-occurring amino acid such as H, - CH 3 , -CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -CHCH 3 -CH 2 -CH 3 , -CH 2 -C 6 H 5 , -CH 2 CH 2 - S-CH 3 , -CH 2 OH, -CH(OH)-CH 3 , -CH 2 -SH, -CH 2 -C 6 H 4 OH, -CH 2 -CO-NH , - CH 2 -CH 2 -CO-NH 2 , -CH2-COOH, -CH 2 -CH 2 -COOH, -(CH 2 ) 4 -NH 2 and -
- Rio also includes l-guanidinoprop-3-yl, benzyl, 4- hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.
- Another set of protecting groups include the residue of an amino- containing compound, in particular an amino acid, a polypeptide, a protecting group, -NHSO2R NHC(O)R, -N(R)2, NH2 or -NH(R)(H), whereby for example a carboxylic acid is reacted, i.e. coupled, with the amine to form an amide, as in C(O)NR 2 .
- a phosphonic acid may be reacted with the amine to form a phosphonamidate, as in -P(O)(OR)(NR 2 ).
- amino acids have the structure R 17 C(O)CH(R l6 )NH-, where R 17 is -OH, -OR, an amino acid or a polypeptide residue.
- Amino acids are low molecular weight compounds, on the order of less than about 1000 MW and which contain at least one amino or imino group and at least one carboxyl group.
- the amino acids will be found in nature, i.e., can be detected in biological material such as bacteria or other microbes, plants, animals or man.
- Suitable amino acids typically are alpha amino acids, i.e. compounds characterized by one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom.
- hydrophobic residues such as mono-or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parental drug. Typically, the residue does not contain a sulfhydryl or guanidino substituent.
- Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally- occurring amino acid residues.
- amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline.
- unnatural amino acids for example, valanine, phenylglycine and homoarginine are also included.
- Commonly encountered amino acids that are not gene- encoded may also be used in the present invention. All of the amino acids used in the present invention may be either the D- or L- optical isomer.
- protecting groups are single amino acid residues or polypeptides they optionally are substituted at R 3 of substituents A 1 , A 2 or A 3 in Formula I.
- These conjugates are produced by forming an amide bond between a carboxyl group of the amino acid (or C-terminal amino acid of a polypeptide for example).
- conjugates are formed between R 3 (Formula I) and an amino group of an amino acid or polypeptide.
- R 3 Forma I
- only one of any site in the parental molecule is amidated with an amino acid as described herein, although it is within the scope of this invention to introduce amino acids at more than one permitted site.
- a carboxyl group of R 3 is amidated with an amino acid.
- the ⁇ -amino or ⁇ -carboxyl group of the amino acid or the terminal amino or carboxyl group of a polypeptide are bonded to the parental functionalities, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates as described further below).
- carboxyl-containing side chains of amino acids or polypeptides it will be understood that the carboxyl group optionally will be blocked, e.g., by R 1 , esterified with R 5 or amidated. Similarly, the amino side chains R 16 optionally will be blocked with R 1 or substituted with R 5 .
- esters or amide bonds with side chain amino or carboxyl groups like the esters or amides with the parental molecule, optionally are hydrolyzable in vivo or in vitro under acidic (pH ⁇ 3) or basic (pH >10) conditions. Alternatively, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments.
- the esters or amino acid or polypeptide amidates also are useful as intermediates for the preparation of the parental molecule containing free amino or carboxyl groups.
- the free acid or base of the parental compound for example, is readily formed from the esters or amino acid or polypeptide conjugates of this invention by conventional hydrolysis procedures.
- any of the D, L, meso, threo or erythro (as appropriate) racemates, scalemates or mixtures thereof may be used.
- D isomers are useful.
- L isomers are more versatile since they can be susceptible to both non-enzymatic and enzymatic hydrolysis, and are more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract.
- R x or R y examples include the following:
- Aminopolycarboxylic acids e.g., aspartic acid, ⁇ -hydroxyaspartic acid, glutamic acid, ⁇ -hydroxyglutamic acid, ⁇ -methylaspartic acid, ⁇ -methylglutamic acid, ⁇ , ⁇ -dimethylaspartic acid, ⁇ -hydroxyglutamic acid, ⁇ , ⁇ -dihydroxyglutamic acid, ⁇ -phenylglutamic acid, ⁇ -methyleneglutamic acid, 3-aminoadipic acid, 2- aminopimelic acid, 2-aminosuberic acid and 2-aminosebacic acid;
- Amino acid amides such as glutamine and asparagine
- Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine, ⁇ -aminoalanine, ⁇ -aminobutyrine, ornithine, citruline, homoarginine, homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid;
- Diaminodicarboxylic acids such as ⁇ , ⁇ '-diaminosuccinic acid, ⁇ , ⁇ '- diaminoglutaric acid, ⁇ , ⁇ '-diaminoadipic acid, ⁇ , ⁇ '-diaminopimelic acid, ⁇ , ⁇ '- diamino- ⁇ -hydroxypimelic acid, ⁇ , ⁇ '-diaminosuberic acid, ⁇ , ⁇ '-diaminoazelaic acid, and ⁇ , ⁇ '-diaminosebacic acid;
- Imino acids such as proline, hydroxyproline, allohydroxyproline, ⁇ - methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2- carboxylic acid;
- a mono- or di-alkyl (typically -Cs branched or normal) amino acid such as alanine, valine, leucine, allylglycine, butyrine, norvaline, norleucine, heptyline, ⁇ -methylserine, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxyvaleric acid, ⁇ -amino- ⁇ - methyl- ⁇ -hydroxyvaleric acid, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxycaproic acid, • isovaline, ⁇ -methylglutamic acid, ⁇ -aminoisobutyric acid, ⁇ -aminodiethylacetic acid, ⁇ -aminodiisopropylacetic acid, ⁇ -aminodi-n-propylacetic acid, ⁇ - aminodiisobutylacetic acid, ⁇ -aminodi-n-butylacetic acid, ⁇ - aminoethylisopropylacetic acid, ⁇ -
- Aliphatic ⁇ -amino- ⁇ -hydroxy acids such as serine, ⁇ -hydroxyleucine, ⁇ - hydroxynorleucine, ⁇ -hydroxynorvaline, and ⁇ -amino- ⁇ -hydroxystearic acid; ⁇ -Amino, ⁇ -, ⁇ -, ⁇ - or ⁇ -hydroxy acids such as homoserine, ⁇ - hydroxynorvaline, ⁇ -hydroxynorvaline and ⁇ -hydroxynorleucine residues; canavine and canaline; ⁇ -hydroxyornithine;
- 2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic acid
- ⁇ -Amino- ⁇ -thiols such as penicillamine, ⁇ -thiolnorvaline or ⁇ - thiolbutyrine
- cysteine Other sulfur containing amino acid residues including cysteine; homocystine, ⁇ -phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2- thiolhistidine, cystathionine, and thiol ethers of cysteine or homocysteine;
- Phenylalanine, tryptophan and ring-substituted ⁇ -amino acids such as the phenyl- or cyclohexylamino acids ⁇ -aminophenylacetic acid, ⁇ - aminocyclohexylacetic acid and ⁇ -amino- ⁇ -cyclohexylpropionic acid; phenylalanine analogues and derivatives comprising aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dichloro, o-, m- or/7-methyl-, 2,4,6- trimethyl-, 2-ethoxy-5 -nitro-, 2-hydroxy-5 -nitro- and p-nitro-phenylalanine); furyl-, thienyl-,
- Polypeptides are polymers of amino acids in which a carboxyl group of one amino acid monomer is bonded to an amino or imino group of the next amino acid monomer by an amide bond.
- Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000 MW) and proteins. Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are substantially sequence-homologous with human, animal, plant or microbial proteins. They include enzymes (e.g., hydrogen peroxidase) as well as immunogens such as KLH, or antibodies or proteins of any type against which one wishes to raise an immune response. The nature and identity of the polypeptide may vary widely.
- polypeptide amidates are useful as immunogens in raising antibodies against either the polypeptide (if it is not immunogenic in the animal to which it is administered) or against the epitopes on the remainder of the compound of this invention.
- Antibodies capable of binding to the parental non-peptidyl compound are used to separate the parental compound from mixtures, for example in diagnosis or manufacturing of the parental compound.
- the conjugates of parental compound and polypeptide generally are more immunogenic than the polypeptides in closely homologous animals, and therefore make the polypeptide more immunogenic for facilitating raising antibodies against it. Accordingly, the polypeptide or protein may not need to be immunogenic in an animal typically used to raise antibodies, e.g., rabbit, mouse, horse, or rat, but the final product conjugate should be immunogenic in at least one of such animals.
- the polypeptide optionally contains a peptidolytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom. Such cleavage sites are flanked by enzymatic recognition structures, e.g., a particular sequence of residues recognized by a peptidolytic enzyme.
- Peptidolytic enzymes for cleaving the polypeptide conjugates of this invention are well known, and in particular include carboxypeptidases.
- Carboxypeptidases digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C-terminal sequences.
- Such enzymes and their substrate requirements in general are well known.
- a dipeptide (having a given pair of residues and a free carboxyl terminus) is covalently bonded through its ⁇ -amino group to the phosphorus or carbon atoms of the compounds herein.
- Wl is phosphonate it is expected that this peptide will be cleaved by the appropriate peptidolytic enzyme, leaving the carboxyl of the proximal amino acid residue to autocatalytically cleave the phosphonoamidate bond.
- Suitable dipeptidyl groups are AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, Rl, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, C
- Tripeptide residues are also useful as protecting groups.
- the sequence -X 4 -pro-X 5 - (where X 4 is any amino acid residue and X 5 is an amino acid residue, a carboxyl ester of proline, or hydrogen) will be cleaved by luminal carboxypeptidase to yield X 4 with a free carboxyl, which in turn is expected to autocatalytically cleave the pphhoosspphhconoamidate bond.
- the carboxy group of X 5 optionally is esterified with benzyl.
- Dipeptide or tripeptide species can be selected on the basis of known transport properties and/or susceptibility to peptidases that can affect transport to intestinal mucosal or other cell types.
- Dipeptides and tripeptides lacking an ⁇ - amino group are transport substrates for the peptide transporter found in brush border membrane of intestinal mucosal cells (Bai, J.P.F., (1992) Pharm Res. 9:969-978).
- Transport competent peptides can thus be used to enhance bioavailability of the amidate compounds.
- Di- or tripeptides having one or more amino acids in the D configuration are also compatible with peptide transport and can be utilized in the amidate compounds of this invention.
- Amino acids in the D configuration can be used to reduce the susceptibility of a di- or tripeptide to hydrolysis by proteases common to the brush border such as aminopeptidase N.
- di- or tripeptides alternatively are selected on the basis of their relative resistance to hydrolysis by proteases found in the lumen of the intestine.
- tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase A
- di- or tripeptides lacking amino acid residues on the N-terminal side of hydrophobic amino acids are poor substrates for endopeptidase
- peptides lacking a pro residue at the penultimate position at a free carboxyl terminus are poor substrates for carboxypeptidase P.
- Similar considerations can also be applied to the selection of peptides that are either relatively resistant or relatively susceptible to hydrolysis by cytosolic, renal, hepatic, serum or other peptidases.
- Such poorly cleaved polypeptide amidates are immunogens or are useful for bonding to proteins in order to prepare immunogens.
- the conjugate is a compound that is substituted with one or more phosphonate groups either directly or indirectly through a linker; and that is optionally substituted with one or more groups A 0 ; or a pharmaceutically acceptable salt thereof, wherein:
- a 0 is A 1 , A 2 or W 3 ;
- a 1 is:
- a 2 is:
- a 3 is:
- Y 1 is independently O, S, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R X )( R x ));
- Y 2 is independently a bond, O, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R X )( R x )), -S(O)M2-, or -S(O) M2 -S(O) M 2-;
- R x is independently H, R 1 , W 3 , a protecting group, or the formula:
- R y is independently H, W 3 , R 2 or a protecting group
- R 1 is independently H or alkyl of 1 to 18 carbon atoms
- R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R groups or taken together at a carbon atom, two R groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups;
- R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R d ;
- R > 3 J a a is F, CI, Br, I, -CN, N 3 or -NO 2 ;
- R 3b is Y'
- R 3c is -R x , -N(R X )(R X ), -SR X , -S(O)R x , -S(O) 2 R x , -S(O)(OR x ),
- R 3d is -C(Y')R X , -C(Y')OR x or -C(Y')(N(R X )(R X ));
- R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
- R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
- R 5 is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 3 groups; W 3 is W 4 or W 5 ;
- W 4 is R 5 , -C(Y')R 5 , -C(Y')W 5 , -SO 2 R 5 , or -SO 2 W 5 ;
- W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
- W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups
- M2 is 0, 1 or 2;
- M12a is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- Mia, Ml c, and Mid are independently 0 or 1 ;
- M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12.
- a 1 is of the formula:
- W a is a carbocycle or a heterocycle where W a is independently substituted with 0 or 1 R 2 groups.
- a specific velue for Ml 2a is 1.
- a 1 is of the formula:
- a 1 is of the formula:
- Y 2b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
- a 1 is of the formula:
- W 5a is a carbocycle independently substituted with 0 or 1 R 2 groups;
- a 1 is of the formula:
- W 5a is a carbocycle or heterocycle where W 5a is independently substituted with 0 or 1 R 2 groups.
- a 1 is of the formula:
- Y 2b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
- a 2 is of the formula:
- Ml 2b is 1.
- Y 2 is a bond and W 5 is a carbocycle or heterocycle where W 5 is optionally and independently substituted with 1, 2, or 3 R 2 groups.
- a 2 is of the formula:
- W 5a is a carbocycle or heterocycle where W 5a is optionally and independently substituted with 1, 2, or 3 R 2 groups.
- Ml 2a is 1.
- a 2 is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl.
- a 2 is of the formula:
- Ml 2b is 1.
- A is of the formula:
- a 3 is of the formula:
- M12 wherein Y 2b is O or N(R X ); and Ml 2d is 1, 2, 3, 4, 5, 6, 7 or 8.
- a 3 is of the formula:
- M12d wherein Y 2b is O or N(R X ); and Ml 2d is 1, 2, 3, 4, 5, 6, 7 or 8.
- Ml 2d is 1.
- a 3 is of the formula:
- W 5 i,s a carbocycle.
- a 3 is of the formula:
- W is phenyl
- a 3 is of the formula:
- Y la is O or S; and Y 2a is O, N(R X ) or S.
- a 3 is of the formula:
- Y 2b is O or N(R X ).
- a 3 is of the formula:
- Y b is O or N(R x ); and Ml 2d is 1, 2, 3, 4, 5, 6, 7 or 8.
- R 1 is H.
- a 3 is of the formula:
- phenyl carbocycle is substituted with 0, 1, 2, or 3 R groups.
- a 3 is of the formula:
- a 3 is of the formula:
- a 3 is of the formula:
- Y rl'a a is O or S
- Y / 2'b D is O or N(R')
- Y 2c c is O, N(R y ) or S.
- a 3 is of the formula:
- a 3 is of the formula:
- Y' B is O or N(R'); and Ml 2d is 1, 2, 3, 4, 5, 6, 7 or 8.
- a 3 is of the formula:
- Y 2b is O or N(R 2 ).
- Y la is O or S; and Y 2a is O, N(R 2 ) or S.
- A is of the formula:
- Y 2b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
- Y 2b is O or N(R 2 ).
- a 3 is of the formula:
- Y 2b is O or N(R X ); and Ml 2d is 1, 2, 3, 4, 5, 6, 7 or 8.
- a 3 is of the formula:
- phenyl carbocycle is substituted with 0, 1, 2, or 3 R groups.
- a 3 is of the formula:
- phenyl carbocycle is substituted with 0, 1, 2, or 3 R groups.
- a 3 is of the formula:
- A is of the formula: wherein each R is independently (C ⁇ -C6)alkyl.
- R x is independently H, R 1 , W 3 , a protecting group, or the formula:
- R y is independently H, W , R or a protecting group
- R 1 is independently H or alkyl of 1 to 18 carbon atoms
- R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3
- Y la is O or S; and Y 2c is O, N(R y ) or S.
- Y la is O or S; and Y 2d is O or N(R y ).
- R y is hydrogen or alkyl of 1 to 10 carbons.
- Y 1 is O or S
- Y 2 is O, N(R y ) or S.
- M1a M1b M12c M1c M1d M1e wherein: m la, mlb, mlc, mid and mle are independently 0 or 1; ml2c is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- R y is H, W 3 , R 2 or a protecting group; provided that: if mla, ml2c, and mid are 0, then mlb, mlc and mle are 0; if mla and ml2c are 0 and mid is not 0, then mlb and mlc are 0; if mla and mid are 0 and ml2c is not 0, then mlb and at least one of mlc and mle are 0; if m la is 0 and ml2c and mid are not 0, then mlb is 0; if ml2c and mid are 0 and mla is not 0, then at least two of mlb, mlc and mle are 0; if m 12c is 0 and m 1 a and m 1 d are not 0, then at least one of m 1 b and mlc are 0; and if mid is 0 and mla and
- DRUG is a compound of any one of formulae 500-601: nn is 1, 2, or 3;
- a 0 is A 1 , A 2 or W 3 with the proviso that the compound includes at least one A 1
- a 1 is:
- a 2 is:
- a 3 is:
- Y 1 is independently O, S, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R X )( R x ));
- Y 2 is independently a bond, O, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R X )( R x )), -S(O)M2-, or -S(O) M2 -S(O) M2 -;
- R x is independently H, R 1 , W 3 , a protecting group, or the formula:
- R y is independently H, W 3 , R 2 or a protecting group;
- R' is independently H or alkyl of 1 to 18 carbon atoms;
- R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups;
- R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
- R 3a is F, CI, Br, I, -CN, N 3 or -NO 2 ;
- R 3b is Y';
- R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
- R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
- R 5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 3 groups;
- W 3 is W 4 or W 5 ;
- W 4 is R 5 , -C(Y')R 5 , -C(Y')W 5 , -SO 2 R 5 , or -SO 2 W 5 ;
- W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
- W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups; M2 is 0, 1 or 2; M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12
- M 1 a, M 1 c, and M 1 d are independently 0 or 1
- M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
- the invention provides a compound of the formula 1-336:
- a 0 is A
- a 1 is:
- a 3 is:
- Y 1 is independently O, S, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R X )( R x ));
- Y 2 is independently a bond, O, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R X )( R x )), -S(O)M 2 -, or -S(O) M2 -S(O) M2 -;
- R x is independently H, W 3 , a protecting group, or the formula:
- R y is independently H, W 3 , R or a protecting group
- R 1 is independently H or alkyl of 1 to 18 carbon atoms
- R 2 is independently H, R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups;
- R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
- R , 3 J a a is F, CI, Br, I, -CN, N 3 or -NO 2 ;
- R 3b is Y'
- R 3c is -R x , -N(R X )(R X ), -SR X , -S(O)R x , -S(O) 2 R x , -S(O)(OR x ),
- R 3d is -C(Y')R X , -C(Y')OR x or -C(Y')(N(R X )(R X ));
- R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
- R ,5 is R wherein each R >4 • is substituted with 0 to 3 R groups;
- R , 5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 3 groups;
- W 3 is W 4 or W 5 ;
- W 4 is R 5 , -C(Y')R 5 , -C(Y')W 5 , -SO 2 R 5 , or -SO 2 W 5 ;
- W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
- W 6 is W 3 independently substituted with 1 , 2, or 3 A 3 groups
- M2 is 0, 1 or 2;
- M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- M12b is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- Mla, Ml c, and Mid are independently 0 or 1 ;
- M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12.
- a 0 is A 1 ;
- A' is:
- a 3 is:
- Y 1 is independently O, S, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R X )( R x ));
- Y 2 is independently a bond, O, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R X )( R x )), -S(O) M 2-, or -S(O) M 2-S(O) M2 -;
- R x is independently H, W , a protecting group, or the formula:
- R y is independently H, W , R or a protecting group
- R 1 is independently H or alkyl of 1 to 18 carbon atoms
- R 2 is independently H, R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups;
- R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
- R >3 j a a is F, CI, Br, I, -CN, N 3 or -NO 2 ;
- R 3b is Y'
- R 3c is -R x , -N(R X )(R X ), -SR X , -S(O)R x , -S(O) 2 R x , -S(O)(OR x ),
- R 3d is -C(Y')R X , -C(Y')OR x or -C(Y')(N(R X )(R X ));
- R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
- R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
- R 5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 3 groups;
- W 3 is W 4 or W 5 ;
- W 4 is R 5 , -C(Y')R 5 , -C(Y')W 5 , -SO 2 R 5 , or -SO 2 W 5 ;
- W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
- W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups
- M2 is 0, 1 or 2;
- M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12
- M 1 a, M 1 c, and M 1 d are independently 0 or 1
- M12c is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12.
- the invention provides a compound of the formula:
- DRUG is a compound of any one of 500-601;
- Y 1 is independently O, S, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R X )( R x ));
- Y 2 is independently a bond, O, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R X )( R x )), -S(O)M2-, or -S(O) M2 -S(O) M2 -;
- R y is independently H, W 3 , R n 2 or a protecting group
- R 2 is independently H, R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups;
- R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
- R 3a is F, CI, Br, I, -CN, N 3 or -NO 2 ;
- R 3b is Y'
- R 3c is -R x , -N(R X )(R X ), -SR X , -S(O)R x , -S(O) 2 R x , -S(O)(OR x ), - S(O) 2 (OR x ), -OC(Y')R x , -OC(Y')OR x , -OC(Y')(N(R x )(R x )), -SC(Y')R X , -SC(Y')OR x , -SC(Y')(N(R X )(R X )), -N(R X )C(Y')R X , -N(R x )C(Y')OR x , or - N(R X )C(Y')(N(R X )(R X )) ;
- R j ⁇ is -C(Y')R X , -C(Y')OR x or -C(Y')(N(R X )(R X ));
- R is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
- R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
- W 3 is W 4 or W 5 ;
- W 4 is R 5 , -C(Y')R 5 , -C(Y')W 5 , -SO 2 R 5 , or -SO 2 W 5 ;
- W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
- M2 is 1, 2, or 3;
- Mla, Mlc, and Mid are independently 0 or 1 ;
- the invention provides a compound of which is a compound of the formula:
- DRUG is a compound of any one of formulae 500-601; nn is 1, 2, or 3;
- a 0 is A 1 , A 2 , or W 3 with the proviso that the compound includes at least one A
- a 2 is:
- Y 1 is independently O, S, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R X )( R x ));
- Y 2 is independently a bond, O, N(R X ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R X )( R x )), -S(O) M2 -, or -S(O) M2 -S(O) M2 -;
- R y is independently H, W 3 , r R> 2 or a protecting group
- R 2 is independently H, R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups;
- R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
- R 3a is F, CI, Br, I, -CN, N 3 or -NO 2 ;
- R 3b is Y'
- R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
- W 3 is W 4 or W 5 ;
- W 4 is R 5 , -C(Y')R 5 , -C(Y')W 5 , -SO 2 R 5 , or -SO 2 W 5 ;
- W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
- W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups
- M2 is 0, 1 or 2;
- M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
- M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
- Mla, Mlc, and Mid are independently 0 or 1 ;
- M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12.
- W 5 carbocycles and W 5 heterocycles may be independently substituted with 0 to 3 R 2 groups.
- W 5 may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle.
- W 5 may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms.
- the W 5 rings are saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4 ring atoms, saturated, or mono- or di-unsaturated when containing 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic when containing 6 ring atoms.
- a W 5 heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S).
- W 5 heterocyclic monocycles may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S).
- W 5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
- the W 5 heterocycle may be bonded to Y 2 through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.
- W heterocycles include for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl.
- W 5 also includes, but is not limited to, examples such as:
- W carbocycles and heterocycles may be independently substituted with
- substituted W 5 carbocycles include:
- substituted phenyl carbocycles include:
- the invention provides a conjugate of Formula I:
- B is selected from adenine, guanine, cytosine, uracil, thymine, 7- deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6- chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, 0 6 -methylguanine, N ⁇ -methyladenine, (T'-methylthymine, 5,6-dihydrothymine, 5,
- Z 2 is selected from H, C
- Y 2 is independently a bond, O, CR 2 , NR, ⁇ (OXR), N(OR), ⁇ NCOXOR), N-NR 2 , S, S-S, S(O), or S(O) 2 ;
- M2 is 0, 1 or 2;
- R is independently R y , a protecting group, or the formula:
- Mla, Mlc, and Mid are independently 0 or 1 ;
- M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12; and R is C ⁇ -C 8 alkyl, C,-C 8 substituted alkyl, C,-C 8 alkenyl, G-C 8 substituted alkenyl, C ⁇ -C 8 alkynyl, G-C 8 substituted alkynyl, C 6 -C 20 aryl, C ⁇ -C 2 o substituted aryl, C 2 -C 2 o heterocycle, C 2 -C o substituted heterocycle, or a protecting group; and
- W 3 is W 4 or W 5 , where W 4 is R, -C(Y')R y , -C(Y')W 5 , -SO 2 R y , or - SO 2 W 5 ; and W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups.
- C]-C 8 substituted alkyl, C ⁇ -C 8 substituted alkenyl, C ( -C 8 substituted alkynyl, C 6 -C 20 substituted aryl, and C 2 -C 2 o substituted heterocycle are independently substituted with one or more substituents selected from F, CI, Br, I, OH, -NH 2 , -NH 3 + , -NHR, -NR 2 , -NR 3 + , G-C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C
- protecting group is selected from a carboxyl ester, a carboxamide, an aryl ether, an alkyl ether, a trialkylsilyl ether, a sulfonic acid ester, a carbonate, and a carbamate.
- W 5 is selected from the structures:
- X is O and R y is H.
- Z 1 is OH.
- Z 2 is C
- Z 2 is CH 3 .
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- Z 1 is OH
- Z 2 is C ⁇ -C 8 alkyl or G-C 8 substituted alkyl
- Z 2 is CH 3 .
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- R >2 is H or C ⁇ -C 8 alkyl.
- the conjugate of formula I has the following formula:
- the conjugate of formula I has the following formula:
- Y c is O, N(R y ) or S.
- the conjugate of formula I has the following formula:
- Y 2c is O; Y 2c is N(CH 3 ); and R y is H or C ⁇ -C 8 alkyl.
- the substituted triazole has the structure:
- the conjugate of Formula I is a conjugate of the following formula:
- B is selected from adenine, guanine, cytosine, uracil, thymine, 7- deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6- chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, 0 6 -methylguanine, N'-methyladenine, O ⁇ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4- methylindole
- Z 2 is selected from H, C ⁇ -C 8 alkyl, C ⁇ -C substituted alkyl, C
- R is C
- W 3 is W 4 or W 5 , where W 4 is R, -C(Y')R y , -C(Y')W 5 , -SO 2 R y , or - SO 2 W 5 ; and W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups.
- the conjugate of Formula I has the following formula:
- PG is a protecting group selected from an ether-forming group, a thioether-forming group, an ester-forming group, a thioester- forming group, a silyl-ether forming group, an amide-forming group, an acetal-forming group, a ketal-forming group, a carbonate-forming group, a carbamate-forming group, a urea-forming group, an amino acid conjugate, and a polypeptide conjugate.
- the invention provides a conjugate of
- B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8- azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4- thiothymine, 4-thiouracil, ⁇ 9 6 -methylguanine, N ⁇ -methyladenine, O 4 - methylthymine, 5,6-dihydrothymine
- the invention provides a conjugate of
- B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 2,6-diaminopurine, 5- fluorocytosine, or c-propyl-2,6-diaminopurine.
- the compound is isolated and purified.
- the invention provides a conjugate of Formula I having one of the following formulae:
- the compound is isolated and purified.
- the invention provides a conjugate of Formula I having one of the following formulae:
- B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8- azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4- thiothymine, 4-thiouracil, 0 d -methylguanine, N ⁇ -methyladenine, O 4 - methylthymine, 5,6-dihydrothymine
- the invention provides a conjugate of Formula I having one of the following formulae:
- B is adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 2,6-diaminopurine, 5- fluorocytosine, or c-propyl-2,6-diaminopurine.
- the compound is isolated and purified.
- the invention provides a conjugate of Formula I having one of the following formulae:
- the compound is isolated and purified.
- the invention provides a conjugate of Formula II:
- B is selected from adenine, guanine, cytosine, uracil, thymine, 7- deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6- chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, ( -methylguanine, N ⁇ -methyladenine, Cr'-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4- methylindole, substitute
- X is selected from O, C(R y ) 2 , OC(R y ) 2 , NR and S;
- Z 1 is independently selected from H, OH, OR, NR 2 , CN, NO 2 , SH, SR, F, CI, Br, and I;
- Z 2 is selected from H, C
- Y 1 is independently O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N-NR 2 ;
- Y 2 is independently a bond, O, CR 2 , NR, + N(O)(R), N(OR), + (O)(OR),
- M2 is 0, 1 or 2;
- Mla, Mlc, and Mid are independently 0 or 1 ;
- M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12; and R is C ⁇ -C 8 alkyl, C ⁇ -C 8 substituted alkyl, C ⁇ -C 8 alkenyl, C ⁇ -C 8 substituted alkenyl, C ⁇ -C 8 alkynyl, C ⁇ -C 8 substituted alkynyl, C6-C 20 aryl, C 6 -C 2 o substituted aryl, C 2 -C 2 o heterocycle, C 2 -C 0 substituted heterocycle, or a protecting group; and
- W 3 is W 4 or W 5 , where W 4 is R, -C(Y')R y , -C(Y')W 5 , -SO 2 R y , or - SO 2 W 5 ; and W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups.
- C)-C 8 substituted alkyl, C ⁇ -C 8 substituted alkenyl, C ⁇ -C 8 substituted alkynyl, C ⁇ -C 2 o substituted aryl, and C 2 -C 2 o substituted heterocycle are independently substituted with one or more substituents selected from F, CI, Br, I, OH, -NH 2 , -NH 3 + , -NHR, -NR 2 , -NR 3 + , Cj-C ⁇ alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, -C 8 alkylsulfonate, C ⁇ -C 8 alkylamino, 4- dialkylaminopyridinium, C ⁇ -C 8 alkylhydroxyl, C ⁇ -C 8 alkylthiol, -SO 2 R, -SO 2 Ar, -SO
- protecting group is selected from a carboxyl ester, a carboxamide, an aryl ether, an alkyl ether, a trialkylsilyl ether, a sulfonic acid ester, a carbonate, and a carbamate.
- W 5 is selected from the structures:
- X is O and
- R y is H.
- the conjugate of Formula II has the following formula:
- the conjugate of Formula II has the following formula:
- Z 1 is OH; and Z is CH 3 .
- the conjugate of Formula II has the following formula:
- Z is C ⁇ -C 8 alkyl or C ⁇ -C 8 substituted alkyl.
- the conjugate of Formula II has the following formula:
- the conjugate of Formula II has the following formula:
- the conjugate of Formula II has the following formula:
- the conjugate of Formula II has the following formula:
- the conjugate of Formula II has the following formula:
- the conjugate of Formula II has the following formula:
- the conjugate of Formula II has the following formula:
- R is H or C ⁇ C 8 alkyl.
- the conjugate of Formula II has the following formula:
- the conjugate of Formula II has the following formula:
- the conjugate of Formula II has the following formula: wherein, in a more specific embodiment, Y is O; Y is N(CH 3 ).
- the substituted triazole has the structure:
- the conjugate of Formula II has the following formula:
- B is selected from adenine, guanine, cytosine, uracil, thymine, 7- deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6- chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O fi -methylguanine, N ⁇ -methyladenine, ⁇ 3 4 -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4- methyl
- Z 2 is selected from H, -C 8 alkyl, C ⁇ -C 8 substituted alkyl, C ⁇ -C 8 alkenyl, C ⁇ -C 8 substituted alkenyl, C ⁇ -C 8 alkynyl, and C ⁇ -C 8 substituted alkynyl,
- R is C
- W 3 is W 4 or W 5 , where W 4 is R, -C(Y')R y , -C(Y')W 5 , -SO 2 R y , or - SO 2 W 5 ; and W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups.
- the conjugate of Formula II has the following formula:
- PG is a protecting group selected from an ether-forming group, a thioether-forming group, an ester-forming group, a thioester-forming group, a silyl-ether forming group, an amide-forming group, an acetal-forming group, a ketal-forming group, a carbonate-forming group, a carbamate-forming group, a urea-forming group, an amino acid conjugate, and an olypeptide conjugate
- the invention provides a conjugate of Formula III:
- B is selected from adenine, guanine, cytosine, uracil, thymine, 7- deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6- chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, 0 6 -methylguanine, N ⁇ -methyladenine, C ⁇ -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4- methylindole
- Y 1 is independently O, S, NR, ⁇ (OXR), N(OR), + N(O)(OR), or N-NR 2 ;
- Y 2 is independently O, CR 2 , NR, ⁇ N(O)(R), N(OR), + N(O)(OR), N-NR 2 , S, S-S, S(O), or S(O) 2 ;
- M2 is 0, 1 or 2;
- R x is independently R y , a protecting group, or the formula:
- Mla, Mlc, and Mid are independently 0 or 1;
- M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and R is C
- W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups.
- C ⁇ -C 8 substituted alkyl, C ⁇ -C 8 substituted alkenyl, C ⁇ -C 8 substituted alkynyl, C 6 -C 20 substituted aryl, and C 2 -C 20 substituted heterocycle are independently substituted with one or more substituents selected from F, CI, Br, I, OH, -NH 2 , -NH 3 + , -NHR, -NR 2 , -NR 3 + , C,-C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, - alkylsulfonate, C)-C 8 alkylamino, 4- dialkylaminopyridinium, C ⁇ -C 8 alkylhydroxyl, C ⁇ -C 8 alkylthiol, -SO 2 R, -SO 2 Ar, -SOAr, -SAr
- protecting group is selected from a carboxyl ester, a carboxamide, an aryl ether, an alkyl ether, a trialkylsilyl ether, a sulfonic acid ester, a carbonate, and a carbamate.
- W 5 is selected from the structures:
- X is O and each R y is H.
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Applications Claiming Priority (126)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US46559403P | 2003-04-25 | 2003-04-25 | |
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PCT/US2004/013121 WO2004096235A2 (en) | 2003-04-25 | 2004-04-26 | Anti-cancer phosphonate analogs |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1617848A2 true EP1617848A2 (de) | 2006-01-25 |
Family
ID=36146932
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04750828A Withdrawn EP1617848A2 (de) | 2003-04-25 | 2004-04-26 | Phosphonat konjugate für die behandlung von krebs |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1617848A2 (de) |
KR (1) | KR20060061930A (de) |
AU (1) | AU2004233989A1 (de) |
BR (1) | BRPI0409680A (de) |
WO (1) | WO2004096235A2 (de) |
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EP1633766B1 (de) | 2003-05-30 | 2019-03-06 | Gilead Pharmasset LLC | Modifizierte fluorinierte nukleosidanaloga |
DE602005027466D1 (de) * | 2004-07-27 | 2011-05-26 | Gilead Sciences Inc | Nukleosid phosphonat konjugate als anti hiv mittel |
PL3109244T3 (pl) | 2004-09-14 | 2019-09-30 | Gilead Pharmasset Llc | Wytwarzanie 2'fluoro-2'-alkilo-podstawionych lub innych ewentualnie podstawionych rybofuranozylopirymidyn i puryn oraz ich pochodnych |
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WO2008005542A2 (en) | 2006-07-07 | 2008-01-10 | Gilead Sciences, Inc., | Antiviral phosphinate compounds |
US7964580B2 (en) | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
US8658617B2 (en) | 2008-07-08 | 2014-02-25 | Gilead Sciences, Inc. | Salts of HIV inhibitor compounds |
CN102282155B (zh) | 2008-12-02 | 2017-06-09 | 日本波涛生命科学公司 | 磷原子修饰的核酸的合成方法 |
JP5793084B2 (ja) | 2008-12-23 | 2015-10-14 | ギリアド ファーマセット エルエルシー | プリンヌクレオシドの合成 |
TW201026715A (en) | 2008-12-23 | 2010-07-16 | Pharmasset Inc | Nucleoside phosphoramidates |
MX2011006890A (es) | 2008-12-23 | 2011-07-20 | Pharmasset Inc | Analogos de nucleosidos. |
US8816077B2 (en) | 2009-04-17 | 2014-08-26 | Nektar Therapeutics | Oligomer-protein tyrosine kinase inhibitor conjugates |
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US8618076B2 (en) | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
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IN2012DN00720A (de) | 2009-07-06 | 2015-06-19 | Ontorii Inc | |
PT2552930E (pt) | 2010-03-31 | 2015-11-17 | Gilead Pharmasset Llc | 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihidropirimidin- 1-(2h)-il)-4-fluoro-3-hidroxi-4-metiltetrahidrofuran-2- il)metoxi) (fenoxi)fosforil)amino)propanoato de (s)- isopropilo cristalino |
DK2620428T3 (da) | 2010-09-24 | 2019-07-01 | Wave Life Sciences Ltd | Asymmetrisk hjælpegruppe |
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CN108409820A (zh) | 2011-12-20 | 2018-08-17 | 里博科学有限责任公司 | 作为hcv rna复制抑制剂的4′-叠氮基,3′-氟取代的核苷衍生物 |
DK2872485T3 (da) | 2012-07-13 | 2021-03-08 | Wave Life Sciences Ltd | Asymmetrisk hjælpegruppe |
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LT2950786T (lt) | 2013-01-31 | 2020-03-10 | Gilead Pharmasset Llc | Dviejų antivirusinių junginių preparatų kompozicija |
JP6462659B2 (ja) | 2013-03-15 | 2019-01-30 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 非環式ヌクレオシドホスホン酸ジエステル |
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AU2014272055A1 (en) | 2013-05-16 | 2015-12-24 | Riboscience Llc | 4'-azido, 3'-deoxy-3'-fluoro substituted nucleoside derivatives |
US20180200280A1 (en) | 2013-05-16 | 2018-07-19 | Riboscience Llc | 4'-Fluoro-2'-Methyl Substituted Nucleoside Derivatives as Inhibitors of HCV RNA Replication |
MX2016002185A (es) | 2013-08-27 | 2016-06-06 | Gilead Pharmasset Llc | Formulacion combinada de dos compuestos antivirales. |
KR20220106232A (ko) | 2014-01-16 | 2022-07-28 | 웨이브 라이프 사이언시스 리미티드 | 키랄 디자인 |
AU2015317972B2 (en) | 2014-09-15 | 2019-10-17 | The Regents Of The University Of California | Nucleotide analogs |
US10377782B2 (en) | 2015-09-15 | 2019-08-13 | The Regents Of The University Of California | Nucleotide analogs |
ES2892402T3 (es) | 2017-08-01 | 2022-02-04 | Gilead Sciences Inc | Formas cristalinas de ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-il)-4-fluoro-2,5-dihidrofuran-2-il)oxi)metil)(fenoxi)fosforil)-L-alaninato de etilo para tratar infecciones virales |
EP3684374A4 (de) | 2017-09-21 | 2021-06-16 | Riboscience LLC | 4'-fluor-2'-methyl-substituierte nukleosidderivate als hemmer der hcv-rna-replikation |
CN114127082A (zh) | 2019-05-09 | 2022-03-01 | 阿里戈斯治疗公司 | 作为sting调节剂的经修饰的环状二核苷化合物 |
CA3152258A1 (en) * | 2019-09-27 | 2021-04-01 | Sohail F. Tavazoie | Compositions and methods for treating metastatic gastrointestinal cancer |
-
2004
- 2004-04-26 AU AU2004233989A patent/AU2004233989A1/en not_active Abandoned
- 2004-04-26 KR KR1020057020328A patent/KR20060061930A/ko not_active Application Discontinuation
- 2004-04-26 BR BRPI0409680-0A patent/BRPI0409680A/pt not_active IP Right Cessation
- 2004-04-26 WO PCT/US2004/013121 patent/WO2004096235A2/en active Application Filing
- 2004-04-26 EP EP04750828A patent/EP1617848A2/de not_active Withdrawn
Non-Patent Citations (1)
Title |
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See references of WO2004096235A2 * |
Also Published As
Publication number | Publication date |
---|---|
BRPI0409680A (pt) | 2006-04-18 |
WO2004096235A8 (en) | 2005-02-24 |
KR20060061930A (ko) | 2006-06-08 |
WO2004096235A2 (en) | 2004-11-11 |
AU2004233989A1 (en) | 2004-11-11 |
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