Claims for Patent: 7,553,816

Summary for Patent: 7,553,816

Title:	p-amidobenzylethers in drug delivery agents
Abstract:	Compounds of the formulas LA.sub.n-Z-X--W.sub.wD and BZ-X--W.sub.wD wherein: D is a drug moiety; L is a ligand; B is a blocking group; A is an optional acyl unit; Z is an amino acid or a peptide; X is an aminobenzyl ether self-immolative spacer group; W is an optional second self-immolative group; n is an integer of 0 or 1; and w is an integer of 0 or 1, and compositions of said compounds with pharmaceutically acceptable carrier, diluent and/or excipient, and methods of delivery the drug D via the compounds.
Inventor(s):	Senter; Peter D. (Seattle, WA), Toki; Brian E. (Everett, WA), Jeffrey; Scott (Snohomish, WA)
Assignee:	Seattle Genetics, Inc. (Bothell, WA)
Application Number:	10/252,947
Patent Claims:	1. A compound of the formula: LA.sub.n-Z-X--W.sub.wD wherein: D is a drug moiety; L is a ligand; A is an optional acyl unit; Z is an amino acid or a peptide; X is an aminobenzyl ether self-immolative group; W is an optional second self-immolative group; n is an integer of 0 or 1; w is an integer of 0 or 1; and wherein X forms an ether linkage with W when w is 1 or with D when w is 0. 2. A compound of claim 1, represented by the following formula: ##STR00030## wherein: --O-D is a portion of a drug, where the drug has the formula HO-D; J is a substituent group, and m is 0, 1, 2, 3 or 4; ##STR00031## is situated at an ortho- or para- position with respect to the --CH.sub.2-- group; Z-C(.dbd.O) is an amino acid or a peptide; A is an acyl unit where n is 0 or 1; and L is a ligand. 3. A compound of claim 1, represented by the following formula: ##STR00032## wherein: T-D is a portion of a drug, where the drug has the formula HT-D; T is O, S, NH, or N(lower alkyl); J is a substituent group, and m is 0, 1, 2; 3 or 4; ##STR00033## is situated at an ortho- or para- position with respect to the --CH.sub.2-- group; Z-C(.dbd.O) is an amino acid or a peptide; A is an acyl unit and n is 0 or 1; L is a ligand; p is 1 or 2; and each of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is independently selected from H and C.sub.1-C.sub.5 alkyl. 4. A compound of claim 2 wherein the O of --O-D is bonded to a carbon that forms an aromatic ring of D. 5. A compound of claim 4 wherein the drug is 1,2,9,9a-tetra-hydro-cyclo-propa[c]benz[e]indol-4-one (CBI) conjugated to a minor groove binder. 6. A compound of claim 4 wherein the drug is cyclopropapyrroloindole (CPI) conjugated to a minor groove binder. 7. A compound of claim 4 wherein the drug is 1,2,9,9a-tetra-hydro-cyclo-propa[c]pyrido[3,2-e]indol-4-one (CPyI) conjugated to a minor groove binder. 8. A compound of claim 4 wherein the drug is selected from: U-76,073; seco-adozelesin; bizelesin; 1,2,9,9a-tetra-hydro-cyclo-propa[c]benz[e]indol-4-one-trimethoxyindole (CBI-TMI); duocarmycin C2; duocarmycin B2; seco-CC-1065; pancratistatin; carminomycin; streptonigrin; zorubicin; elliptinium acetate; mitoxantrone; daunorubicin; phenol mustard; doxorubicin; etoposide, combretastatin A-4, and 7-ethyl-10-hydroxycamptothecin (SN-38). 9. A compound of claim 2 wherein the O of --O-D is bonded to an aliphatic carbon of D. 10. A compound of claim 9 in which the drug is auristatin E. 11. A compound of claim 2 wherein the H of H--O-D has a pKa of 16 or less. 12. A compound of claim 3 wherein T is NH or N(lower alkyl). 13. A compound of claim 3 wherein T is O or S. 14. A compound of claim 12 wherein the drug is selected from 5-amino-1,2,9,9a-tetra-hydro-cyclopropa[c]benz[e]indol-4-one (CBI) conjugated to a minor groove binder; 5-amino-cyclopropapyrroloindole (CPI) conjugated to a minor groove binder; and 5-amino-1,2,9,9a-tetra-hydro-cyclopropa[c]pyrido[3,2-e]indol-4-one (CPyI) conjugated to a minor groove binder. 15. A compound of claim 12 wherein the drug is an amino containing drug moiety selected from the group consisting of mitomycin-C, mitomycin-A, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, aminopterin, actinomycin, bleomycin, 9-amino camptothecin, N.sup.8-acetyl spermidine, 1-(2 chloroethyl)-1,2-dimethanesulfonyl hydrazide, tallysomycin, and derivatives thereof. 16. A compound of claim 13 wherein the drug is auristatin E. 17. A compound of claim 13 wherein the drug is a hydroxyl containing drug moiety selected from the group consisting of: etoposide, camptothecin, taxol, esperamicin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyne-13-one, anguidine, doxorubicin, morpholino-doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, vincristine, vinblastine and derivatives thereof. 18. A compound of claim 13 wherein the drug is a sulfhydryl-containing moiety selected from the group consisting of esperamicin, 6-mercaptopurine, and derivatives thereof. 19. A compound of claim 2 wherein L is an immunoglobulin, or an antigen-binding fragment thereof. 20. A compound of claim 3 wherein L is an immunoglobulin, or an antigen-binding fragment thereof. 21. A compound of claim 19 wherein L is an mAb selected from the group consisting of BR96, L6, trastuzumab, rituximab, S2C6, AC10, and antigen-binding fragments thereof. 22. A compound of claim 20 wherein L is an mAb selected from the group consisting of BR96, L6, trastuzumab, rituximab, S2C6, AC10, and antigen-binding fragments thereof. 23. A compound of claim 2 wherein L is selected from the group consisting of bombesin, EGF, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TFG-.alpha., TFG-.beta., VGF, insulin and insulin-like growth factors I and II, carbohydrates, lectins, and apoprotein from low-density lipoproteins. 24. A compound of claim 3 wherein L is selected from the group consisting of bombesin, EGF, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TFG-.alpha., TFG-.beta., VGF, insulin and insulin-like growth factors I and II, carbohydrates, lectins, and apoprotein from low-density lipoproteins. 25. A compound of claim 2 wherein L is selected from the group consisting of poly(ethylene glycol); poly(propylene glycol); (hydroxypropyl)methacrylamide; chitins; dextrans; styrene-co-maleic acid/anhydride, polyglutamic acid and polylysine. 26. A compound of claim 3 wherein L is selected from the group consisting of poly(ethylene glycol); poly(propylene glycol); (hydroxypropyl)methacrylamide; chitins; dextrans; styrene-co-maleic acid/anhydride, polyglutamic acid and polylysine. 27. A compound of claim 2 wherein m is 0. 28. A compound of claim 3 wherein m is 0. 29. A compound of claim 2 wherein m is 1 and the substituent is an electron-withdrawing group selected from F, Cl, Br, CN, CF.sub.3, CONH.sub.2, CHO, CO.sub.2CH.sub.3, COCH.sub.3, NHCOCH.sub.3, NO.sub.2, and sulfonyl groups. 30. A compound of claim 3 wherein m is 1 and the substituent is an electron-withdrawing group selected from F, Cl, Br, CN, CF.sub.3, CONH.sub.2, CHO, CO.sub.2CH.sub.3, COCH.sub.3, NHCOCH.sub.3, NO.sub.2, and sulfonyl groups. 31. A compound of claim 2 wherein Z is a dipeptide or a tripeptide. 32. A compound of claim 3 wherein Z is a dipeptide or a tripeptide. 33. A compound of claim 2 wherein Z is valine-citrulline. 34. A compound of claim 3 wherein Z is valine-citrulline. 35. A compound of claim 2 wherein Z is phenylalanine-lysine. 36. A compound of claim 3 wherein Z is phenylalanine-lysine. 37. A compound of claim 2 wherein ##STR00034## situated at the para- position with respect to the --CH2-- group. 38. A compound of claim 3 wherein ##STR00035## is situated at the para- position with respect to the --CH.sub.2-- group. 39. A compound of claim 2 wherein n is 1. 40. A compound of claim 3 wherein n is 1. 41. A compound of claim 39 wherein A is ##STR00036## and q is 1-10. 42. A compound of claim 40 wherein A is ##STR00037## and q is 1-10. 43. A compound of claim 41 where q=5. 44. A compound of claim 42 where q=5. 45. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient. 46. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 2 and a pharmaceutically acceptable carrier, diluent or excipient. 47. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 3 and a pharmaceutically acceptable carrier, diluent or excipient. 48. The compound of claim 1 wherein: D is ##STR00038## L is cAC10; A is an optional acyl unit; Z is -val-lys-; X is ##STR00039## W is an optional second self-immolative group; n is an integer of 0 or 1; w is an integer of 0 or 1; and MGB is a DNA minor groove binder. 49. The compound of claim 48 wherein L is cAC10; A is ##STR00040## and w is 0. 50. The compound of claim 49 having the formula ##STR00041## 51. The compound of claim 48 wherein MGB is (S)-N-[2-[[1-(chloromethyl)-1,6-dihydro-5-hydroxy-8-methylbenzo[1,2-b:4,3- -b']dipyrrol-3(2-yl]carbonyl]-1H-indol-5-yl]-6-(diethylamino)-2-benzofuran- carboxamide(U-76,073); seco-adozelesin; bizelesin; 1,2,9,9a-tetra-hydro-cyclo-propa[c]benz[e]indol-4-one-trimethoxyindole (CBI-TMI); duocarmycin C2; duocarmycin B2; or benzo(1,2-b:4,3-b')dipyrrole-3(2H)-carboxamide, 7-((1,6-dihydro-4-hydroxy-5-methoxy-7-((4,5,8,8a-tetrahydro-7-methyl-4-ox- ocyclopropa.COPYRGT.pyrrolo(3,2-e)indol-2-(1H)-yl)carbonyl)benzo(1,2-b:4,3- -b')dipyrrol-3(2H)-yl)carbonyl)-1,6-dihydro-4-hydroxy-5-methoxy-,(7bR)(sec- o-CC-1065).

Details for Patent 7,553,816

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2021-09-24
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2021-09-24
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2021-09-24
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2021-09-24
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2021-09-24