Claims for Patent: 9,504,669

Summary for Patent: 9,504,669

Title:	Spliceostatin analogs and methods for their preparation
Abstract:	The present invention is directed to novel cytotoxic spliceostatin analogs and derivatives, to antibody drug conjugates thereof, and to methods for using the same to treat medical conditions including cancer.
Inventor(s):	Subramanyam; Chakrapani (South Glastonbury, CT), Koehn; Frank Erich (Mystic, CT), Dirico; Kenneth John (Gales Ferry, CT), Eustaquio; Alessandra S. (Old Saybrook, CT), Green; Michael Eric (Boston, MA), He; Haiyin (Mahwah, NJ), He; Min (North Potomac, MD), O\'Donnell; Christopher John (Mystic, CT), Puthenveetil; Sujiet (North Attleboro, MA), Ratnayake; Anokha (Mystic, CT), Teske; Jesse Alexander (Westerly, RI), Yang; Hui Yu (Newton, MA)
Assignee:	Pfizer Inc. (New York, NY)
Application Number:	14/818,455
Patent Claims:	1. A method for treating cancer comprising administering to a patient an amount of a compound of formula (I): ##STR00319## wherein: a dashed line represents an optional bond; each X.sup.1 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X.sup.2 is independently selected from the group consisting of: --O--, --S-- and --NR--; R.sup.1 is selected from the group consisting of: --R, --OR, --OCOR.sup.13, --OCONR.sup.14R.sup.15, --OCON(R.sup.14)NR(R.sup.15), .dbd.O (double bond to oxygen) and --NR.sup.14R.sup.15; R.sup.2 and R.sup.3 are independently selected from the group consisting of: hydrogen and C.sub.1-6alkyl; R.sup.4 and R.sup.5 are independently selected from the group consisting of: hydrogen, --OR, --NR.sup.14R.sup.15 and oxo; R.sup.6 and R.sup.7 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl and C.sub.1-6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and halogen, R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a C.sub.2-5alkylidene optionally substituted with 1-3 substituents independently selected from R, R.sup.6 and R.sup.7 together are oxo, or R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R; R.sup.8 is hydrogen, C.sub.1-6alkyl or --OR; R.sup.9 is independently selected from --(C(R).sub.2).sub.m--C(O)OR, --(C(R).sub.2).sub.m--C(O)NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--N(R)COR.sup.13, --(C(R).sub.2).sub.m--C(O)--SR, --(C(R).sub.2).sub.m--C(O)NR.sup.14N(R)R.sup.15, --(C(R).sub.2).sub.m--NR--C(O)--NR.sup.14R.sup.15 and (C(R).sub.2).sub.m--NR.sup.14N(R)R.sup.15; R.sup.13 is selected from the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.3-8carbocyclyl, C.sub.3-8heterocyclyl, C.sub.1-6alkyl-C.sub.6-14aryl, C.sub.1-6alkyl-O.sub.5-14heteroaryl, wherein R.sup.13 is optionally substituted with --NRR or --SO.sub.2NRR; each R.sup.14 and R.sup.15 is independently selected from the group consisting of: hydrogen, hydroxyl, --NRR, --NRNR.sub.2, --C.sub.3-10carbocyclyl, --C.sub.1-6alkylene-C.sub.3-10carbocyclyl, --C.sub.3-10heterocyclyl, --C.sub.1-6alkylene-C.sub.3-10heterocyclyl, --(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2C(O)OR, --(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2NRR, --C.sub.1-6alkyl, C.sub.6-14aryl, --C.sub.1-6alkylene-C.sub.6-14aryl and --C.sub.5-14heteroaryl; or R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, wherein R.sup.14, R.sup.15, or both, or a ring formed with R.sup.14 and R.sup.15, are optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --(C(R).sub.2).sub.m--NRR or --(C(R).sub.2).sub.m--SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6 cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, --(C(R).sub.2).sub.m--O--NRR and --S--S--C.sub.1-6alkyl-NRR; each R is independently selected from the group consisting of: hydrogen and --C.sub.1-6alky; and each m is independently 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof, said amount being effective to that cancer. 2. The method of claim 1 where said cancer is selected from carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, skin, stomach, and testes, leukemias and lymphomas. 3. The method of claim 2 wherein said compound is selected from the group consisting of: ##STR00320## ##STR00321## ##STR00322## ##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332## ##STR00333## or a pharmaceutically acceptable salt thereof. 4. A method for treating cancer comprising administering to a patient an amount of a compound having the formula III: (AB)-(L-P).sub.b (III) or a pharmaceutically acceptable salt thereof, wherein: L is the linker moiety L.sup.1-L.sup.2-L.sup.3, where L.sup.3 is bound to P; P is a radical of formula (I): ##STR00334## wherein: a dashed line represents an optional bond; AB is an antibody; each X.sup.1 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X.sup.2 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X' is CR or N; each X'' is CH--, CR--(C(R).sub.2).sub.m--NR--, CR--(C(R).sub.2).sub.m--O--; CR--(C(R).sub.2).sub.m--C(O)NR--, CR--(C(R).sub.2).sub.m--C(O)NR--NR--, CR--(C(R).sub.2).sub.m--SO.sub.2NR--, CR--(C(R).sub.2).sub.m--NR--NR--, CR--(C(R).sub.2).sub.m--NR--C(O)-- or N-- if X'' binds to L.sup.2 or an additional L.sup.3, or otherwise is O, S, CRR, CR--(C(R).sub.2).sub.m--NRR or NRR; each X''' is --(C(R).sub.2).sub.m--NR-- or CR--(C(R).sub.2).sub.m--O-- if X''' binds to L.sup.2, or otherwise is R; Y is --C(R).sub.2--, --O--, --NR-- or --S--; R.sup.1 is selected from the group consisting of: --R, --OR, --OCOR.sup.13, --OCONR.sup.14R.sup.15, --OCON(R.sup.14)NR(R.sup.15), .dbd.O (double bond to oxygen) and --NR.sup.14R.sup.15; R.sup.2 and R.sup.3 are independently selected from the group consisting of: hydrogen and C.sub.1-6alkyl; R.sup.4 and R.sup.5 are independently selected from the group consisting of: hydrogen, --OR, --NR.sup.14R.sup.15 and oxo; R.sup.6 and R.sup.7 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl and C.sub.1-6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and halogen, R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a C.sub.2-5alkylidene optionally substituted with 1-3 substituents independently selected from R, R.sup.6 and R.sup.7 together are oxo, or R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R; R.sup.8 is hydrogen, C.sub.1-6alkyl or --OR; R.sup.9 is --(C(R).sub.2).sub.m--C(O)-- or --(C(R).sub.2).sub.m--; L.sup.1 is selected from: a bond to AB, --NR-(bond to AB) and ##STR00335## L.sup.2 is L.sup.2A-L.sup.2B-L.sup.2C or L.sup.2C-L.sup.2B-L.sup.2A where: L.sup.2A comprises one or more components selected from: --O--, --C(O)--, --C(O)NR--, --C(O)--C.sub.1-6alkyl-, --C(O)NRC.sub.1-6alkyl-, --C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--, --C(O)--C.sub.1-6alkyl-NRC(O)--, --C(O)--C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--, --C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--C(O)--, --C.sub.1-6alkyl-S--S--C.sub.1-6alkyl-NRC(O)CH.sub.2--, --C.sub.1-6alkyl-(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)CH.sub.2--, --C(O)--C.sub.1-6alkyl-NRC(O)C.sub.1-6alkyl-, --N.dbd.CR-phenyl-O--C.sub.1-6alkyl-, --N.dbd.CR-phenyl-O--C.sub.1-6alkyl-C(O)--, --C(O)--C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)--, --C(O)--C.sub.1-6alkyl-phenyl-(NR--C(O)--C.sub.1-6alkyl).sub.1-4-, --C(O)--C.sub.1-6alkyl-(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)C.sub.1-6alkyl-- , --C.sub.1-6alkyl-, --S--, --C(O)--C.sub.1-6alkyl-phenyl-NR--, --O--C.sub.1-6alkyl-S--, --C(O)--O--C.sub.1-6alkyl-S-- and (--CH.sub.2--CH.sub.2--O--).sub.1-20, or L.sup.A is absent; L.sup.2B is selected from AA.sub.0-aa, where AA is a natural or non-natural amino acid and aa is 12; and L.sup.2C comprises one or more components selected from: -PABA- and -PABC-, or L.sup.2C is absent; L.sup.3 is selected from one or more of: --C.sub.1-6alkyl-, --NR--C.sub.3-C.sub.8heterocyclyl-NR--, --NR--C.sub.3-C.sub.8carbocyclyl-NR--, --NR--C.sub.1-6alkyl-NR--, --NR-C.sub.1-6alkyl-, --S--, --NR--NR-- and --NR--C(O)--NR-- where the two R groups optionally join to form a 4-10 membered ring, --NR--C.sub.1-6alkyl-phenyl-NR--, --NR--C.sub.1-6alkyl-phenyl-SO.sub.2--NR--, --SO.sub.2--, --NR--C.sub.1-6alkyl-phenyl-C(O)--, ##STR00336## or L.sup.3 is absent; R.sup.13 is selected from the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.3-8carbocyclyl, C.sub.3-8heterocyclyl, C.sub.1-6 alkyl-C.sub.6-14aryl, C.sub.1-6alkyl-C.sub.5-14heteroaryl, wherein R.sup.13 is optionally substituted with --NRR or --SO.sub.2NRR; each R.sup.14 and R.sup.15 is independently selected from the group consisting of: hydrogen, hydroxyl, --NRR, --NRNR.sub.2, --C.sub.3-10carbocyclyl, --C.sub.1-6alkylene-C.sub.3-10carbocyclyl, --C.sub.3-10heterocyclyl, --C.sub.1-6alkylene-C.sub.3-10heterocyclyl, --(CH.sub.2CH.sub.2O).sub.1-6 CH.sub.2CH.sub.2C(O)OR, --(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2NRR, --C.sub.1-6alkyl, C.sub.6-14aryl, --C.sub.1-6alkylene-C.sub.6-14aryl and --C.sub.5-14heteroaryl; or R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, wherein R.sup.14, R.sup.15, or both, or a ring formed with R.sup.14 and R.sup.15, are optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --(C(R).sub.2).sub.m--NRR or --(C(R).sub.2).sub.m--SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6 cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, (xv) --(C(R).sub.2).sub.m--O--NRR and (xiv) --S--S--C.sub.1-6alkyl-NRR; each R is independently selected from the group consisting of: hydrogen and --C.sub.1-6alkyl; and b is 1-20; and each m is independently 0, 1, 2 or 3, said amount being effective to treat cancer. 5. The method of claim 4 wherein said cancer is selected from carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, skin, stomach, and testes, leukemias and lymphomas. 6. A method for treating cancer comprising administering to a patient an amount of a compound having the formula III': (AB)-(L-P').sub.b (III') or a pharmaceutically acceptable salt thereof, wherein: L is the linker moiety L.sup.1-L.sup.2-L.sup.3, where L.sup.3 is bound to P'; P' is a radical of formula (I'): ##STR00337## wherein: a dashed line represents an optional bond; AB is an antibody; each X.sup.1 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X.sup.2 is independently selected from the group consisting of: --O--, --S-- and --NR--; each X' is CR or N; each X'' is CH--, CR--(C(R).sub.2).sub.m--NR--, CR--(C(R).sub.2).sub.m--O--; CR--(C(R).sub.2).sub.m--C(O)NR--, CR--(C(R).sub.2).sub.m--C(O)NR--NR--, CR--(C(R).sub.2).sub.m--SO.sub.2NR--, CR--(C(R).sub.2).sub.m--NR--NR--, CR--(C(R).sub.2).sub.m--NR--C(O)-- or N-- if X'' binds to L.sup.2 or an additional L.sup.3, or otherwise is O, S, CRR, CR--(C(R).sub.2).sub.m--NRR or NRR; each X''' is --(C(R).sub.2).sub.m--NR-- or CR--(C(R).sub.2).sub.m--O-- if X''' binds to L.sup.2, or otherwise is R; Y is --C(R).sub.2--, --O--, --NR-- or --S--; R.sup.1 is selected from the group consisting of: --(C(R).sub.2).sub.m--C(O)--, --(C(R).sub.2).sub.m--, --OR'', --OCOR.sup.13', --OCONRR.sup.14', --OCON(R.sup.14)N(R.sup.15)--, and --NR.sup.14-- R.sup.2 and R.sup.3 are independently selected from the group consisting of: hydrogen and C.sub.1-6alkyl; R.sup.4 and R.sup.5 are independently selected from the group consisting of: hydrogen, --OR, --NR.sup.14R.sup.15 and oxo; R.sup.6 and R.sup.7 are independently selected from the group consisting of: hydrogen, halogen, hydroxyl and C.sub.1-6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl and halogen, R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a C.sub.2-5alkylidene optionally substituted with 1-3 substituents independently selected from R, R.sup.6 and R.sup.7 together are oxo, or R.sup.6 and R.sup.7, together with the carbon atom to which they are bound, form a 3- to 5-membered heterocycloalkyl moiety comprising 1 or 2 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted with one to three substituents independently selected from R; R.sup.8 is hydrogen, C.sub.1-6alkyl or --OR; R.sup.9 is independently selected from hydrogen, --C.sub.1-6alkyl, --(C(R).sub.2).sub.m--C(O)OR, --(C(R).sub.2).sub.m--C(O)NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--C(O)--SR, --(C(R).sub.2).sub.m--C(O)NR.sup.14N(R)R.sup.15, --(C(R).sub.2).sub.m--NR--C(O)--NR.sup.14R.sup.15, --(C(R).sub.2).sub.m--NR.sup.14N(R)R.sup.15 and --(C(R).sub.2).sub.m--N(R)COR.sup.13; wherein R.sup.13 is hydrogen or C.sub.1-6alkyl, L.sup.1 is selected from: a bond to AB, --NR-(bond to AB) and ##STR00338## L.sup.2 is L.sup.2A-L.sup.2B-L.sup.2c or L.sup.2c-L.sup.2B-L.sup.2A where: L.sup.2A comprises one or more components selected from: --O--, --C(O)--, --C(O)NR--, --C(O)--C.sub.1-6alkyl-, --C(O)NRC.sub.1-6alkyl-, --C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--, --C(O)--C.sub.1-6alkyl-NRC(O)--, --C(O)--C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--, --C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--C(O)--, --C.sub.1-6alkyl-S--S--C.sub.1-6alkyl-NRC(O)CH.sub.2--, --C.sub.1-6alkyl-(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)CH.sub.2--, --C(O)--C.sub.1-6alkyl-NRC(O)C.sub.1-6alkyl-, --N.dbd.CR-phenyl-O--C.sub.1-6alkyl-, --N.dbd.CR-phenyl-O--C.sub.1-6alkyl-C(O)--, --C(O)--C.sub.1-6alkyl(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)--, --C(O)--C.sub.1-6alkyl-phenyl-(NR--C(O)--C.sub.1-6alkyl).sub.1-4-, --C(O)--C.sub.1-6alkyl-(OCH.sub.2CH.sub.2).sub.1-6--NRC(O)C.sub.1-6alkyl-- , --C.sub.1-6alkyl-, --S--, --C(O)--C.sub.1-6alkyl-phenyl-NR--, --O--C.sub.1-6alkyl-S--, --C(O)--O--C.sub.1-6alkyl-S-- and (--CH.sub.2--CH.sub.2--O--).sub.1-20, or L.sup.A is absent; L.sup.2B is selected from AA.sub.0-aa, where AA is a natural or non-natural amino acid and aa is 12; and L.sup.2C comprises one or more components selected from: -PABA- and -PABC-, or L.sup.2C is absent; L.sup.3 is selected from one or more of: --C.sub.1-6alkyl-, --NR--C.sub.3-C.sub.8heterocyclyl-NR--, --NR--C.sub.3-C.sub.8carbocyclyl-NR--, --S--, --NR--NR-- and --NR--C(O)--NR-- where the two R groups optionally join to form a 4-10 membered ring, --NR--C.sub.1-6alkyl-phenyl-NR--, --NR--C.sub.1-6alkyl-phenyl-SO.sub.2--NR--, --SO.sub.2--, --NR--C.sub.1-6alkyl-phenyl-C(O)--, ##STR00339## or L.sup.3 is absent; R.sup.13' is selected from the group consisting of a bond, --C.sub.1-6alkylene-, --C.sub.3-8carbocyclyl-, --C.sub.3-8 heterocyclyl-, --C.sub.1-6alkyl-C.sub.6-14aryl-, --C.sub.1-6alkyl-C.sub.5-14heteroaryl-; each R.sup.14 and R.sup.15 is independently selected from the group consisting of: hydrogen, hydroxyl, --NRR, --NRNR.sub.2, --C.sub.3-10carbocyclyl, --C.sub.1-6alkylene-C.sub.3-10carbocyclyl, --C.sub.3-10heterocyclyl, --C.sub.1-6alkylene-C.sub.3-10heterocyclyl, --(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2C(O) OR, --(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2NRR, --C.sub.1-6alkyl, C.sub.6-14aryl, --C.sub.1-6alkylene-C.sub.6-14aryl and --C.sub.5-14heteroaryl; or R.sup.14 and R.sup.15, together with the atom or atoms to which they are joined, form a C.sub.3-10heterocyclyl ring, wherein R.sup.14, R.sup.15, or both, or a ring formed with R.sup.14 and R.sup.15, are optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --(C(R).sub.2).sub.m--NRR or C(R).sub.2).sub.m--SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6 cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O) (CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, (xv) --(C(R).sub.2).sub.m--O--NRR and (xiv) --S--S--C.sub.1-6alkyl-NRR; each R.sup.14' is independently selected from the group consisting of: a bond, --NR--, --C.sub.3-10carbocyclyl-, --C.sub.3-10heterocyclyl-, --(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2C(O)OR', --(CH.sub.2CH.sub.2O).sub.1-6CH.sub.2CH.sub.2NR--, and --C.sub.1-6alkylene-, wherein R.sup.14' is optionally substituted with --(C(R).sub.2).sub.m--R.sup.18 where each R.sup.18 is independently selected from (i) --NRR, (ii) --C(NRR)(C(O)OR), (iii) --S--R, (iv) aryl or heteroaryl optionally substituted with one or more of halogen, --CF.sub.3, --NRR or --SO.sub.2NRR, (v) --SO.sub.2R, (vi) --S--S--C.sub.1-6alkyl-C(O)OR, (vii) --SO.sub.2NRR, (viii) --C(O)NRR, (ix) --C(O)OR, (x) --C.sub.4-6 cycloalkyl optionally substituted with --NRR, --SO.sub.2NRR or --NR--C(O)(CH.sub.2).sub.0-6NRR, (xi) --R, (xii) --OR, (xiii) --N(R)NRR, (xiv) --C(O)N(R)NRR, (xv) --(C(R).sub.2).sub.m--O--NRR and (xiv) --S--S--C.sub.1-6alkyl-NRR; each R is independently selected from the group consisting of: hydrogen and --C.sub.1-6alkyl; each R' is independently selected from --H, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 heteroalkyl and aryl; each R'' is independently selected from the group consisting of: a bond and --C.sub.1-6alkylene-; and b is 1-20; and each m is independently 0, 1, 2 or 3, said amount being effective to treat cancer. 7. The method of claim 6, wherein said cancer is selected from carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, skin, stomach, and testes, leukemias and lymphomas. 8. The method of claim 5, wherein said compound is selected from the group consisting of: ##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352## where --NH--X, --NH--C(O)--X or --S--X represents the antibody AB; or a pharmaceutically acceptable salt thereof. 9. The method of claim 5, wherein the antibody AB is selected from: trastuzumab, trastuzumab mutants, oregovomab, edrecolomab, cetuximab, a humanized monoclonal antibody to the vitronectin receptor (.alpha..sub.v.beta..sub.3), alemtuzumab, a humanized anti-HLA-DR antibody for the treatment of non-Hodgkin's lymphoma, 1311 Lym-1, a murine anti-HLA-Dr10 antibody for the treatment of non-Hodgkin's lymphoma, a humanized anti-CD2 mAb for the treatment of Hodgkin's Disease or non-Hodgkin's lymphoma, labetuzumab, bevacizumab, ibritumomab tiuxetan, ofatumumab, panitumumab, rituximab, tositumomab, ipilimumab, gemtuzumab, a humanized monoclonal antibody to the oncofecal protein receptor 5T4, and an antibody to CD11b receptor.

Details for Patent 9,504,669

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
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