Claims for Patent: 6,569,402

Summary for Patent: 6,569,402

Title:	Vitronectin receptor antagonist pharmaceuticals
Abstract:	The present invention describes novel compounds of the formula: useful for the diagnosis and treatment of cancer, methods of imaging tumors in a patient, and methods of treating cancer in a patient. The present invention also provides novel compounds useful for monitoring therapeutic angiogenesis treatment and destruction of new angiogenic vasculature. The present invention further provides novel compounds useful for imaging atherosclerosis, restenosis, cardiac ischemia and myocardial reperfusion injury. The present invention still further provides novel compounds useful for the treatment of rheumatoid arthritis. The pharmaceuticals are comprised of a targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety. The imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.
Inventor(s):	Cheesman; Edward H. (Lunenberg, MA), Barrett; John A. (Groton, MA), Carpenter, Jr.; Alan P. (Carlisle, MA), Rajopadhye; Milind (Westford, MA), Sworin; Michael (Tyngsboro, MA)
Assignee:	Bristol-Myers Squibb Pharma Company (Princeton, NJ)
Application Number:	09/599,365
Patent Claims:	1. A kit for treating cancer, comprising at least one agent selected from the group consisting of a chemotherapeutic agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and a compound, comprising: a) a targeting moiety; b) a chelator; wherein the targeting moiety is bound to the chelator by 0-1 linking groups, and wherein the targeting moiety is a benzodiazepine that binds to an .alpha.v.beta.3 receptor. 2. A kit according to claim 1 wherein said kit comprises a plurality of separate containers, wherein at least one of said containers contains a compound comprising a targeting moiety and a chelator, wherein the targeting moiety is bound to the chelator, is a benzodiazepine, benzodiazepinedione, or dibenzotrihydroannulene nonpeptide, and binds to a receptor that is upregulated during angiogenesis and the compound has 0-1 linking groups between the targeting moiety and chelator, or a pharmaceutically acceptable salt thereof, and at least another of said containers contains one or more agents selected from the group consisting of a chemotherapeutic agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 3. A kit according to claim 1, wherein the chemotherapeutic agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor. 4. A kit according to claim 1, wherein the chemotherapeutic agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, and lisuride. 5. A kit according to claim 1 wherein the chemotherapeutic agent is selected from the group consisting of oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, and formestane. 6. A kit according to claim 1 wherein the chemotherapeutic agent is selected from the group consisting of interferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor. 7. A kit according to claim 1, wherein radiosensitizer agent is selected from the group consiting of 2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide, N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine, 3-amino-1,2,4-benzotriazine-1,4-dioxide, N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide, 1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and 1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol. 8. A therapeutic radiopharmaceutical composition comprising at least one agent selected from the group consisting of a chemotherapeutic agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, and a radiopharmaceutical comprising: a metal, and a compound, wherein the compound comprises: a) a targeting moiety; b) a chelator capable of chelating the metal; the targeting moiety is bound to the chelator by 0-1 linking groups, and the targeting moiety is a benzodiazepine that binds to an .alpha.v.beta.3 receptor. 9. A therapeutic metallopharmaceutical composition according to claim 8, wherein the chemotherapeutic agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor. 10. A therapeutic metallopharmaceutical composition according to claim 8, wherein radiosensitizer agent is selected from the group consiting of 2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide, N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine, 3-amino-1,2,4-benzotriazine-1,4-dioxide, N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide, 1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and 1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol. 11. A method of treating cancer in a patient comprising: administering to a patient in need thereof at least one agent selected from the group consisting of a chemotherapeutic agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof and a therapeutic radiopharmaceutical comprising a metal selected from the group: 33.sub.p, 125.sub.I, 186.sub.Re, 188.sub.Re, 153.sub.Sm, 166.sub.Ho, 177.sub.Lu, 149.sub.Pm, 90.sub.y, 212.sub.Bi, 103.sub.Pd, 109.sub.Pd, 159.sub.Gd, 140.sub.La, 198.sub.Au, 199.sub.Au, 169.sub.Yb, 175.sub.Yb, 165.sub.Dy, 166.sub.Dy, 67.sub.Cu, 105.sub.Rh, 111.sub.Ag, and 192.sub.Ir, and a compound of the formula: wherein, Q is ##STR144## R.sup.1 and R.sup.3 are independently selected from the group: C.sub.1 -C.sub.6 alkyl, benzyl, phenethyl, and a bond to L.sub.n ; provided that one of R.sup.1 and R.sup.3 is a bond to L.sub.n ; R.sup.2 is independently selected from the group: 2-benzimidazolylmethyl, 2-guanidinoethyl, 2-amino-2-pyridyl, 2-amino-2-pyridylmethyl, 5-amino-2-imidazolylmethyl, and 2-imidazolylmethyl; R.sup.4 is independently selected from H, C.sub.1-6 alkyl or benzyl; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; d' is 1-100; L.sub.n is a linking group having the formula: 12. A method of treating cancer according to claim 11, wherein the administration is by injection or infusion. 13. A method according to claim 11 wherein administering the therapeutic radiopharmaceutical and agent is concurrent. 14. A method according to claim 11 wherein administering the therapeutic radiopharmaceutical and agent is sequential. 15. A method according to claim 11 wherein the cancer is selected from the group consisting of carcinomas of the lung, breast, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas, melanomas, gliomas, and neuroblastomas. 16. A method according to claim 11 wherein the chemotherapeutic agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, interferon-alpha, interferon-2 alpha, interferon-beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor. 17. A method according to claim 11 wherein the radiosensitizer agent is selected from the group consisting of 2-(3-nitro-1,2,4-triazol-1-yl)-N-(2-methoxyethyl)acetamide, N-(3-nitro-4-quinolinyl)-4-morpholinecarboxamidine, 3-amino-1,2,4-benzotriazine-1,4-dioxide, N-(2-hydroxyethyl)-2-nitroimidazole-1-acetamide, 1-(2-nitroimidazol-1-yl)-3-(1-piperidinyl)-2-propanol, and 1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol. 18. A kit according to claim 1, wherein compound is of the formula: wherein, Q is ##STR147## R.sup.1 and R.sup.3 are independently selected from the group: C.sub.1 -C.sub.6 alkyl, benzyl, phenethyl, and a bond to L.sub.n ; provided that one of R.sup.1 and R.sup.3 is a bond to L.sub.n ; R.sup.2 is independently selected from the group: 2-benzimidazolylmethyl, 2-guanidinoethyl, 2-amino-2-pyridyl, 2-amino-2-pyridylmethyl, 5-amino-2-imidazolylmethyl, and 2-imidazolylmethyl; R.sup.4 is independently selected from H, C.sub.1-6 alkyl or benzyl; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; d' is 1-100; L.sub.n is a linking group having the formula: 19. A kit according to claim 18, wherein: d is selected from 1, 2, 3, 4 and 5; d' is 1-50; W is independently selected at each occurrence from the group: O, NH, NHC(.dbd.O), C(.dbd.O)NH, NR.sup.8 C(.dbd.O), C(.dbd.O)N R.sup.8, C(.dbd.O), C(.dbd.O)O, OC(.dbd.O), NHC(.dbd.S)NH, NHC(.dbd.O)NH, SO.sub.2, (OCH.sub.2 CH.sub.2).sub.s, (CH.sub.2 CH.sub.2 O).sub.s', (OCH.sub.2 CH.sub.2 CH.sub.2).sub.s", (CH.sub.2 CH.sub.2 CH.sub.2 O).sub.t, and (aa).sub.t' ; aa is independently at each occurrence an amino acid; Z is selected from the group: aryl substituted with 0-1 R.sup.10, C.sub.3-10 cycloalkyl substituted with 0-1 R.sup.10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R.sup.10 ; R.sup.6, R.sup.6a, R.sup.7, R.sup.7a, and R.sup.8 are independently selected at each occurrence from the group: H, .dbd.O, COOH, SO.sub.3 H, C.sub.1 -C.sub.5 alkyl substituted with 0-1 R.sup.10, aryl substituted with 0-1 R.sup.10, benzyl substituted with 0-1 R.sup.10, and C.sub.1 -C.sub.5 alkoxy substituted with 0-1 R.sup.10, NHC(.dbd.O)R.sup.11, C(.dbd.O)NHR.sup.11, NHC(.dbd.O)NHR.sup.11, NHR.sup.1, R.sup.11, and a bond to C.sub.h ; k is 0 or 1; s is selected from 0, 1,2,3,4, and 5; s' is selected from 0, 1, 2, 3, 4, and 5; s" is selected from 0, 1, 2, 3, 4, and 5; t is selected from 0, 1, 2, 3, 4, and 5; A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, A.sup.7, and A.sup.8 are independently selected at each occurrence from the group: NR.sup.13, NR.sup.13 R.sup.14, S, SH, S(Pg), OH, and a bond to L.sub.n ; E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.17, aryl substituted with 0-3 R.sup.17, C.sub.3-10 cycloalkyl substituted with 0-3 R.sup.17, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R.sup.17 ; R.sup.13, and R.sup.14 are each independently selected from the group: a bond to L.sub.n, hydrogen, C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.17, aryl substituted with 0-3 R.sup.17, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R.sup.17, and an electron, provided that when one of R.sup.13 or R.sup.14 is an electron, then the other is also an electron; alternatively, R.sup.13 and R.sup.14 combine to form .dbd.C(R.sup.20)(R.sup.21); R.sup.17 is independently selected at each occurrence from the group: a bond to L.sub.n, .dbd.O, F, Cl, Br, I, --CF.sub.3, --CN, --CO.sub.2 R.sup.18, --C(.dbd.O)R.sup.18, --C(.dbd.O)N(R.sup.18).sub.2, --CH.sub.2 OR.sup.18, --OC(.dbd.O)R.sup.18, --OC(.dbd.O)OR.sup.18a, --OR.sup.18, --OC(.dbd.O)N(R.sup.18).sub.2, --NR.sup.19 C(.dbd.O)OR.sup.18, --NR.sup.19 C(.dbd.O)OR.sup.18a, --NR.sup.19 C(.dbd.O)N(R.sup.18).sub.2, --NR.sup.19 SO.sub.2 N(R.sup.18).sub.2, --NR.sup.19 SO.sub.2 R.sup.18a, --SO.sub.3 H, --SO.sub.2 R.sup.18a, --S(.dbd.O)R.sup.18a, --SO.sub.2 N(R.sup.18).sub.2, --N(R.sup.18).sub.2, --NHC(.dbd.S)NHR.sup.18, .dbd.NOR.sup.18, --C(.dbd.O)NHNR.sup.18 R.sup.18a, --OCH.sub.2 CO.sub.2 H, and 2-(1-morpholino)ethoxy; R.sup.18, R.sup.18a, and R.sup.19 are independently selected at each occurrence from the group: a bond to L.sub.n, H, and C.sub.1 -C.sub.6 alkyl; R.sup.20 and R.sup.21 are independently selected from the group: H, C.sub.1 -C.sub.5 alkyl, --CO.sub.2 R.sup.25, C.sub.2 -C.sub.5 1-alkene substituted with 0-3 R.sup.23, C.sub.2 -C.sub.5 1-alkyne substituted with 0-3 R.sup.23, aryl substituted with 0-3 R.sup.23, and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R.sup.23 ; alternatively, R.sup.20 and R.sup.21, taken together with the divalent carbon radical to which they are attached form: ##STR150## R.sup.22 and R.sup.23 are independently selected from the group: H, and R.sup.24 ; alternatively, R.sup.22, R.sup.23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O; R.sup.24 is independently selected at each occurrence from the group: --CO.sub.2 R.sup.25, --C(.dbd.O)N(R.sup.25).sub.2, --CH.sub.2 OR.sup.25, --OC(.dbd.O)R.sup.25, --OR.sup.25, --SO.sub.3 H, --N(R.sup.25).sub.2, and --OCH.sub.2 --CO.sub.2 H; and, R.sup.25 is independently selected at each occurrence from the group: H and C.sub.1 -C.sub.3 alkyl. 20. A kit according to claim 19, wherein: ##STR151## A.sup.1 is selected from the group: OH, and a bond to L.sub.n ; A.sup.2, A.sup.4, and A.sup.6 are each N; A.sup.3, A.sup.5, and A.sup.8 are each OH; A.sup.7 is a bond to L.sub.n or NH-bond to L.sub.n ; E is a C.sub.2 alkyl substituted with 0-1 R.sup.17 ; R.sup.17 is .dbd.O; alternatively, C.sub.h is ##STR152## A.sup.1 is selected from the group: OH, and a bond to L.sub.n ; A.sup.2, A.sup.3 and A.sup.4 are each N; A.sup.5, A.sup.6 and A.sup.8 are each OH; A.sup.7 is a bond to L.sub.n ; E is a C.sub.2 alkyl substituted with 0-1 R.sup.17 ; R.sup.17 is .dbd.O; Y alternatively, Ch is ##STR153## A.sup.1 is NH.sub.2 or N.dbd.C(R.sup.20)(R.sup.21); E is a bond; A.sup.2 is NHR.sup.13 ; R.sup.13 is a heterocycle substituted with R.sup.17, the heterocycle being selected from pyridine and pyrimidine; R.sup.17 is selected from a bond to L.sub.n, C(.dbd.O)NHR.sup.18 and C(.dbd.O)R.sup.18 ; R.sup.18 is a bond to L.sub.n ; R.sup.24 is selected from the group: --CO.sub.2 R.sup.25, --OR.sup.25, --SO.sub.3 H, and --N(R.sup.25).sub.2 ; and, R.sup.25 is independently selected at each occurrence from the group: hydrogen and methyl. 21. A kit according to claim 1, wherein the compound is selected from the group: (S,S,S)-4-(N-(3-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoy l)-5-(carboxymethyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl) -4-(4-carboxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclodecyl )acetylamino)butanoyl amino)butanoic acid; (S)-2-(2,5-diaza-5-(6((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))c arbonylamino)hexyl)-9-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-4-oxo bicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl) acetic acid; (S)-2-(2,5-diaza-9-(N-(6-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridy l))carbonylamino)hexyl)-N-(benzimidazol-2-ylmethyl)carbamoyl)-5-methyl-4-ox obicyclo [5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid; (S,S)-2-(2-aza-2-((5-(N-(1,3-bis(N-(6-(aminohexyl-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)acetic acid)(2-(2,5-diaza-9-(N-(benzimidazol-2-ylmethyl)propyl)carbamoyl)(2-pyrid yl))amino)vinyl)benzenesulfonic acid; (S,S,S)-4-(N-(3-(3,6-diaza-5-(carboxymethyl)-10-(N-(imidazol-2-ylmethyl)-N- benzylcarbamoyl)-4-oxobicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)propyl) carbamoyl)-4-(4-carboxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl) cyclododecyl)acetylamino)butanoylamino) butanoic acid; (S,S)-3-(N-(3-(3,6-diaza-5-(carboxymethyl)-10-(N-(imidazol-2-ylmethyl)-N-be nzylcarbamoyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-3-(2-(1,4,7,10-tetraaza-4, 7,10-tris(carboxyrmethyl)cyclododecyl)acetylamino)propanoic acid; (S,S,S,S,S,S,S,S)-4-(N-1,3-bis(N-3-carboxy-1-(N-(3-(3,6-diaza-10-(N-(benzim idazol-2-ylmethyl)-N-methylcarbamoyl)-5-(carboxymethyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-4,4-dihydroxypentyl)carbam oyl)propyl)carbamoyl)-4-(5,5-dihydroxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris( carboxymethyl)cyclodecyl)acetylamino) butanoic acid; (S,S,S,S,S,S,S,S,S,S)-2-(4-(N-(1,3-bis(N-(3-(N-(3-(3,6-diaza-10-(N-(benzimi dazol-2-ylmethyl)-N-methylcarbamoyl)-5-((methoxycarbonyl)methyl)-4-oxobicyc lo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-1-(methoxycarbonyl)propyl) carbamoyl)propyl)carbamoyl)propyl)carbamoyl)-4-(2-(2-(1,4,7,10-tetraaza-4,7 ,10-tris(carboxymethyl)cyclodecyl)acetylamino)-4-carboxybutanoylamino)-4-ca rboxybutanoylamino)butanoylamino)-4-(N-(3-(3,6-diaza-10-(N-(benzimidazol-2- ylmethyl)-N-methylcarbamoyl)-5-((methoxycarbonyl)methyl)-4-oxobicyclo[5.4. 0] undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)butanoic acid; (S)-2-(2,5-diaza-5-(3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3- pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)-9-(N-(benzimidazol-2-y lmethyl)-N-methylcarbamoyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)acetic acid; (S,S,S,S,S)-4-(N-(1,3-bis(N-(3-(2-(2-(3-(3,6-diaza-10-(N-(benzimidazol-2-yl methyl)-N-methylcarbamoyl) -5-(carboxymethyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propy l)carbamoyl)-4-(5,5-dihydroxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxyme thyl)cyclododecyl)acetylamino)hexanoylamino)butanoic acid; (S,S,S)-2-(2,5-diaza-9-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-4-ox o-5-(6-(4-(N-((R,S,S,S)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl)-2-(4-(N-((R, S,S,S)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl)-2-(2-(1,4,7,10-tetraaza-4,7,1 0-tris(carboxymethyl)cyclodecyl)acetylamino)butanoylamino)butanoylamino)hex yl)bicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid; (S,S,S,S)-2-(4-(N-(1-(N-(1-(N-(6-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl) -N-methylcarbamoyl)-5-(carboxymethyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)hexyl)carbamoyl)-3-(N-cyclo{Lys-Arg(Mtr)-Gly -Asp(OtBu)-D-Phe}[gamma-LySNH]carbamoyl)propyl)carbamoyl)-3-carboxypropyl)c arbamoyl)-4-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)ac etylamino)butanoic acid; 4-[N-(3-{(2R)-7-[N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl]-2-(carboxym ethyl)-3-oxo(1H, 2H,5H-benzof[f]1,4-diazepin-4-yl)}propyl)carbamoyl](4S)-4-[(4S)-4-(N-{(1S) -1-[N-(3-{(2S)-7-[N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl]-2-(carboxy methyl)-3-oxo (1H,2H,5H-benzo[f]1,4-diazepin-4-yl)}propyl)carbamoyl]-3-carboxypropyl}car bamoyl)-4-{2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]acet ylamino}butanoylamino]butanoic acid; 2-(4-{3-[(6-{[(1E)-1-aza-2-(2-sulfophenyl)vinyl]amino}(3-pyridyl))carbonyla mino]propyl}(2S)-7-{N-[2-(amidinoamino)ethyl]-N-methylcarbamoyl}-3-oxo-1H,2 H,5H-benzo[f]1,4-diazepin-2-yl)acetic acid; and 2-[9-(N-{6-[(6-{[(1E)-1-aza-2-(2-sulfophenyl)vinyl]amino}(3-pyridyl))carbon ylamino]hexyl}-N-(benzimidazol-2-ylmethyl)carbamoyl)(5S)-5,6,11-trihydrodib enzo[b,e][7]annulen-5-yl]acetic acid; or a pharmaceutically acceptable salt form thereof. 22. A therapeutic radiopharmaceutical composition according to claim 8, wherein compound is of the formula: wherein, Q is ##STR154## R.sup.1 and R.sup.3 are independently selected from the group: C.sub.1 -C.sub.6 alkyl, benzyl, phenethyl, and a bond to L.sub.n ; provided that one of R.sup.1 and R.sup.3 is a bond to L.sub.n ; R.sup.2 is independently selected from the group: 2-benzimidazolylmethyl, 2-guanidinoethyl, 2-amino-2-pyridyl, 2-amino-2-pyridylmethyl, 5-amino-2-imidazolylmethyl, and 2-imidazolylmethyl; R.sup.4 is independently selected from H, C.sub.1-6 alkyl or benzyl; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; d' is 1-100; L.sub.n is a linking group having the formula: and, R.sup.25, R.sup.25a, and R.sup.26 are each independently selected at each occurrence from the group: hydrogen and C.sub.1 -C.sub.6 alkyl; and a pharmaceutically acceptable salt thereof. 23. A therapeutic radiopharmaceutical composition according to claim 22, wherein: d is selected from 1, 2, 3, 4, and 5; d' is 1-50; W is independently selected at each occurrence from the group: O, NH, NHC(.dbd.O), C(.dbd.O)NH, NR.sup.8 C(.dbd.O), C(.dbd.O)N R.sup.8, C(.dbd.O), C(.dbd.O)O, OC(.dbd.O), NHC(.dbd.S)NH, NHC(.dbd.O)NH, SO.sub.2, (OCH.sub.2 CH.sub.2).sub.s, (CH.sub.2 CH.sub.2 O).sub.s', (OCH.sub.2 CH.sub.2 CH.sub.2).sub.s", (CH.sub.2 CH.sub.2 CH.sub.2 O).sub.t, and (aa).sub.t' ; aa is independently at each occurrence an amino acid; Z is selected from the group: aryl substituted with 0-1 R.sup.10, C.sub.3-10 cycloalkyl substituted with 0-1 R.sup.10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R.sup.10 ; R.sup.6, R.sup.6a, R.sup.7, R.sup.7a, and R.sup.8 are independently selected at each occurrence from the group: H, .dbd.O, COOH, SO.sub.3 H, C.sub.1 -C.sub.5 alkyl substituted with 0-1 R.sup.10, aryl substituted with 0-1 R.sup.10, benzyl substituted with 0-1 R.sup.10, and C.sub.1 -C.sub.5 alkoxy substituted with 0-1 R.sup.10, NHC(.dbd.O)R.sup.11, C(.dbd.O)NHR.sup.11, NHC(.dbd.O)NHR.sup.11, NHR.sup.11, R.sup.11, and a bond to C.sub.h ; k is 0 or 1; s is selected from 0, 1, 2, 3, 4, and 5; s' is selected from 0, 1, 2, 3, 4, and 5; s" is selected from 0, 1, 2, 3, 4, and 5; t is selected from 0, 1, 2, 3, 4, and 5; A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, A.sup.7, and A.sup.8 are independently selected at each occurrence from the group: NR.sup.13, NR.sup.13 R.sup.14, S, SH, S(Pg), OH, and a bond to L.sub.n ; E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.17, aryl substituted with 0-3 R.sup.17, C.sub.3-10 cycloalkyl substituted with 0-3 R.sup.17, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R.sup.17 ; R.sup.13, and R.sup.14 are each independently selected from the group: a bond to L.sub.n, hydrogen, C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.17, aryl substituted with 0-3 R.sup.17, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R.sup.17, and an electron, provided that when one of R.sup.13 or R.sup.14 is an electron, then the other is also an electron; alternatively, R.sup.13 and R.sup.14 combine to form .dbd.C(R.sup.20)(R.sup.21); R.sup.17 is independently selected at each occurrence from the group: a bond to L.sub.n, .dbd.O, F, Cl, Br, I, --CF.sub.3, --CN, --CO.sub.2 R.sup.18, --C(.dbd.O)R.sup.18, --C(.dbd.O)N(R.sup.18).sub.2, --CH.sub.2 OR.sup.18, --OC(.dbd.O)R.sup.18, --OC(.dbd.O)OR.sup.18a, --OR.sup.18, --OC(.dbd.O)N(R.sup.18).sub.2, --NR.sup.19 C(.dbd.O)R.sup.18, --NR.sup.19 C(.dbd.O)OR.sup.18a, --NR.sup.19 C(.dbd.O)N(R.sup.18).sub.2, --NR.sup.19 SO.sub.2 N(R.sup.18).sub.2, --NR.sup.19 SO.sub.2 R.sup.18a, --SO.sub.3 H, --SO.sub.2 R.sup.18a, --S(.dbd.O)R.sup.18a, --SO.sub.2 N(R.sup.18).sub.2, --N(R.sup.18 ).sub.2, --NHC(.dbd.S)NHR.sup.18, .dbd.NOR.sup.18, --C(.dbd.O)NHNR.sup.18 R.sup.18a, --OCH.sub.2 CO.sub.2 H, and 2-(1-morpholino)ethoxy; R.sup.18, R.sup.18a, and R.sup.19 are independently selected at each occurrence from the group: a bond to L.sub.n, H, and C.sub.1 -C.sub.6 alkyl; R.sup.20 and R.sup.21 are independently selected from the group: H, C.sub.1 -C.sub.5 alkyl, --CO.sub.2 R.sup.25, C.sub.2 -C.sub.5 1-alkene substituted with 0-3 R.sup.23, C.sub.2 -C.sub.5 1 -alkyne substituted with 0-3 R.sup.23, aryl substituted with 0-3 R.sup.23, and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R.sup.23 ; alternatively, R.sup.20 and R.sup.21, taken together with the divalent carbon radical to which they are attached form: ##STR157## R.sup.22 and R.sup.23 are independently selected from the group: H, and R.sup.24 ; alternatively, R.sup.22, R.sup.23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O; R.sup.24 is independently selected at each occurrence from the group: --CO.sub.2 R.sup.25, --C(.dbd.O)N(R.sup.25).sub.2, --CH.sub.2 OR.sup.25, --OC(.dbd.O)R.sup.25, --OR.sup.25, --SO.sub.3 H, --N(R.sup.25).sub.2, and --OCH.sub.2 CO.sub.2 H; and, R.sup.25 is independently selected at each occurrence from the group: H and C.sub.1 -C.sub.3 alkyl. 24. A therapeutic radiopharmaceutical composition according to claim 23, wherein: ##STR158## A.sup.1 is selected from the group: OH, and a bond to L.sub.n ; A.sup.2, A.sup.4, and A.sup.6 are each N; A.sup.3, A.sup.5, and A.sup.8 are each OH; A.sup.7 is a bond to L.sub.n or NH-bond to L.sub.n ; E is a C.sub.2 alkyl substituted with 0-1 R.sup.17 ; R.sup.17 is .dbd.O; alternatively, C.sub.h is ##STR159## A.sup.1 is selected from the group: OH, and a bond to L.sub.n ; A.sup.2, A.sup.3 and A.sup.4 are each N; A.sup.5, A.sup.6 and A.sup.8 are each OH; A.sup.7 is a bond to L.sub.n ; E is a C.sub.2 alkyl substituted with 0-1 R.sup.17 ; R.sup.17 is .dbd.O; alternatively, C.sub.h is ##STR160## A.sup.1 is NH.sub.2 or N.dbd.C(R.sup.20) (R.sup.21); E is a bond; A.sup.2 is NHR.sup.13 ; R.sup.13 is a heterocycle substituted with R.sup.17, the heterocycle being selected from pyridine and pyrimidine; R.sup.17 is selected from a bond to L.sub.n, C(.dbd.O)NHR.sup.18 and C(.dbd.O)R.sup.18 ; R.sup.18 is a bond to L.sub.n ; R.sup.24 is selected from the group: --CO.sub.2 R.sup.25, --OR.sup.25, --SO.sub.3 H, and --N(R.sup.25).sub.2 ; and, R.sup.25 is independently selected at each occurrence from the group: hydrogen and methyl. 25. A therapeutic radiopharmaceutical composition according to claim 8, wherein the compound is selected from the group consisting of: (S,S,S)-4-(N-(3-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoy l)-5-(carboxymethyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-4-(4-carboxy-2-(2-(1,4,7,1 0-tetraaza-4,7,10-tris(carboxymethyl)cyclodecyl)acetylamino)butanoyl amino)butanoic acid; (S)-2-(2,5-diaza-5-(6((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))c arbonylamino)hexyl)-9-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-4-oxo bicyclo [5.4.0]undeca-1(7),8,10-trien-3-yl) acetic acid; (S)-2-(2,5-diaza-9-(N-(6-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridy l))carbonylamino)hexyl)-N-(benzimidazol-2-ylmethyl)carbamoyl)-5-methyl-4-ox obicyclo (5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid; (S,S)-2-(2-aza-2-((5-(N-(1,3-bis(N-(6-(aminohexyl-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)acetic acid)(2-(2,5-diaza-9-(N-(benzimidazol-2-ylmethyl)propyl)carbamoyl)(2-pyrid yl))amino)vinyl) benzenesulfonic acid; (S,S,S) -4-(N-(3-(3, 6-diaza-5-(carboxymethyl)-10-(N-(imidazol-2-ylmethyl)-N-benzylcarbamoyl)-4 -oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-4-(4-carboxy-2-(2-(1,4,7,1 0-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)butanoylamino )butanoic acid; (S,S)-3-(N-(3-(3,6-diaza-5-(carboxymethyl)-10-(N-(imidazol-2-ylmethyl)-N-be nzylcarbamoyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-3-(2-(1,4,7,10-tetraaza-4, 7,10-tris(carboxymethyl)cyclododecyl)acetylamino)propanoic acid; (S,S,S,S,S,S,S,S)-4-(N-1,3-bis(N-3-carboxy-1-(N-(3-(3,6-diaza-10-(N-(benzim idazol-2-ylmethyl)-N-methylcarbamoyl)-5-(carboxymethyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-4,4-dihydroxypentyl)carbam oyl)propyl)carbamoyl)-4-(5,5-dihydroxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris( carboxymethyl)cyclodecyl)acetylamino)butanoic acid; (S,S,S,S,S,S,S,S,S,S)-2-(4-(N-(1,3-bis(N-(3-(N-(3-(3,6-diaza-10-(N-(benzimi dazol-2-ylmethyl)-N-methylcarbamoyl)-5-((methoxycarbonyl)methyl)-4-oxobicyc lo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-1-(methoxycarbonyl)propyl) carbamoyl)propyl)carbamoyl)propyl)carbamoyl)-4-(2-(2-(1,4,7,10-tetraaza-4,7 ,10-tris(carboxymethyl) cyclodecyl)acetylamino)-4-carboxybutanoylamino)-4-carboxybutanoylamino)but anoylamino)-4-(N-(3-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl)-N-methyl carbamoyl)-5-((methoxycarbonyl)methyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)butanoic acid; (S)-2-(2,5-diaza-5-(3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3- pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)-9-(N-(benzimidazol-2-y lmethyl)-N-methylcarbamoyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)acetic acid; (S,S,S,S,S)-4-(N-(1,3-bis(N-(3-(2-(2-(3-(3,6-diaza-10-(N-(benzimidazol-2-yl methyl)-N-methylcarbamoyl)-5-(carboxymethyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propy l)carbamoyl)-4-(5,5-dihydroxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxyme thyl)cyclododecyl)acetylamino)hexanoylamino)butanoic acid; (S,S,S)-2-(2,5-diaza-9-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-4-ox o-5-(6-(4-(N-((R,S,S,S)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl)-2-(4-(N-((R, S,S,S)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl)-2-(2-(1,4,7,10-tetraaza-4,7,1 0-tris(carboxymethyl)cyclodecyl)acetylamino)butanoylamino)butanoylamino)hex yl)bicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid; (S,S,S,S)-2-(4-(N-(1-(N-(1-(N-(6-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl) -N-methylcarbamoyl)-5-(carboxymethyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)hexyl)carbamoyl)-3-(N-cyclo{Lys-Arg(Mtr)-Gly -Asp(OtBu)-D-Phe}[gamma-LysNH]carbamoyl)propyl)carbamoyl)-3-carboxypropyl)c arbamoyl)-4-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)ac etylamino)butanoic acid; 4-[N-(3-{(2R)-7-[N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl]-2-(carboxym ethyl)-3-oxo(1H, 2H,5H-benzo[f]1,4-diazepin-4-yl)}propyl)carbamoyl](4S)-4-[(4S)-4-(N-{(1S)- 1-[N-(3-{(2S)-7-[N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl]-2-(carboxym ethyl)-3-oxo (1H,2H,5H-benzo[f]1,4-diazepin-4-yl)}propyl)carbamoyl]-3-carboxypropyl}car bamoyl)-4-{2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]acet ylamino}butanoylamino]butanoic acid; 2-(4-{3-[(6-{[(1E)-1-aza-2-(2-sulfophenyl)vinyl]amino}(3-pyridyl))carbonyla mino]propyl}(2S)-7-{N-[2-{(amidinoamino)ethyl]-N-methylcarbamoyl}-3-oxo-1H, 2H,5H-benzo[f]1,4-diazepin-2-yl)acetic acid; and 2-[9-(N-{6-[(6-{[(1E)-1-aza-2-(2-sulfophenyl)vinyl]amino}(3-pyridyl))carbon ylamino]hexyl}-N-(benzimidazol-2-ylmethyl)carbamoyl)(5S)-5,6,11-trihydro-di benzo[b,e][7]annulen-5-yl]acetic acid; or a pharmaceutically acceptable salt form thereof. 26. A method according to claim 11, wherein: d is selected from 1, 2, 3, 4, and 5; d' is 1-50; W is independently selected at each occurrence from the group: O, NH, NHC(.dbd.O), C(.dbd.O)NH, NR.sup.8 C(.dbd.O), C(.dbd.O)N R.sup.8, C(.dbd.O), C(.dbd.O)O, OC(.dbd.O), NHC(.dbd.S)NH, NHC(.dbd.O)NH, SO.sub.2, (OCH.sub.2 CH.sub.2).sub.s, (CH.sub.2 CH.sub.2 O).sub.s', (OCH.sub.2 CH.sub.2 CH.sub.2).sub.s", (CH.sub.2 CH.sub.2 CH.sub.2 O).sub.t, and (aa).sub.t' ; aa is independently at each occurrence an amino acid; Z is selected from the group: aryl substituted with 0-1 R.sup.10, C.sub.3-10 cycloalkyl substituted with 0-1 R.sup.10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R.sup.10 ; R.sup.6, R.sup.6a, R.sup.7, R.sup.7a, and R.sup.8 are independently selected at each occurrence from the group: H, .dbd.O, COOH, SO.sub.3 H, C.sub.1 -C.sub.5 alkyl substituted with 0-1 R.sup.10, aryl substituted with 0-1 R.sup.10, benzyl substituted with 0-1 R.sup.10, and C.sub.1 -C.sub.5 alkoxy substituted with 0-1 R.sup.10, NHC(.dbd.O)R.sup.11, C(.dbd.O)NHR.sup.11, NHC(.dbd.O)NHR.sup.11, NHR.sup.11, R.sup.11, and a bond to C.sub.h ; k is 0 or 1; s is selected from 0, 1, 2, 3, 4, and 5; s' is selected from 0, 1, 2, 3, 4, and 5; s" is selected from 0, 1, 2, 3, 4, and 5; t is selected from 0, 1, 2, 3, 4, and 5; A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6, A.sup.7, and A.sup.8 are independently selected at each occurrence from the group: NR.sup.13, NR.sup.13 R.sup.14, S, SH, S(Pg), OH, and a bond to L.sub.n ; E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.17, aryl substituted with 0-3 R.sup.17, C.sub.3-10 cycloalkyl substituted with 0-3 R.sup.17, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R.sup.17 ; R.sup.13, and R.sup.14 are each independently selected from the group: a bond to L.sub.n, hydrogen, C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.17, aryl substituted with 0-3 R.sup.17, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R.sup.17, and an electron, provided that when one of R.sup.13 or R.sup.14 is an electron, then the other is also an electron; alternatively, R.sup.13 and R.sup.14 combine to form .dbd.C(R.sup.20)(R.sup.21); R.sup.17 is independently selected at each occurrence from the group: a bond to L.sub.n, .dbd.O, F, Cl, Br, I, --CF.sub.3, --CN, --CO.sub.2 R.sup.18, --C(.dbd.O)R.sup.18, --C(.dbd.O)N(R.sup.18).sub.2, --CH.sub.2 OR.sup.18, --OC(.dbd.O)R.sup.18, OC(.dbd.O)OR.sup.18a, --OR.sup.18, --OC(.dbd.O)N(R.sup.18).sub.2, --NR.sup.19 C(.dbd.O)R.sup.18, --NR.sup.19 C(.dbd.O)OR.sup.18a, --NR.sup.19 C(.dbd.O)N(R.sup.18).sub.2, --NR.sup.19 SO.sub.2 N(R.sup.18).sub.2, --NR.sup.19 SO.sub.2 R.sup.18a, --SO.sub.3 H, --SO.sub.2 R.sup.18a, --S(.dbd.O)R.sup.18a, --SO.sub.2 N(R.sup.18).sub.2, --N(R.sup.18).sub.2, --NHC(.dbd.S)NHR.sup.18, .dbd.NOR.sup.18, --C(.dbd.O)NHNR.sup.18 R.sup.18a, --OCH.sub.2 CO.sub.2 H, and 2-(1-morpholino)ethoxy; R.sup.18, R.sup.18a, and R.sup.19 are independently selected at each occurrence from the group: a bond to L.sub.n, H, and C.sub.1 -C.sub.6 alkyl; R.sup.20 and R.sup.21 are independently selected from the group: H, C.sub.1 -C.sub.5 alkyl, --CO.sub.2 R.sup.25, C.sub.2 -C.sub.5 1-alkene substituted with 0-3 R.sup.23, C.sub.2 -C.sub.5 1-alkyne substituted with 0-3 R.sup.23, aryl substituted with 0-3 R.sup.23, and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R.sup.23 ; alternatively, R.sup.20 and R.sup.21, taken together with the divalent carbon radical to which they are attached form: ##STR161## R.sup.22 and R.sup.23 are independently selected from the group: H, and R.sup.24 ; alternatively, R.sup.22, R.sup.23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O; R.sup.24 is independently selected at each occurrence from the group: --CO.sub.2 R.sup.25, --C(.dbd.O)N(R.sup.25).sub.2, --CH.sub.2 OR.sup.25, --OC(.dbd.O)R.sup.25, --OR.sup.25, --SO.sub.3 H, --N(R.sup.25).sub.2, and --OCH.sub.2 CO.sub.2 H; and, R.sup.25 is independently selected at each occurrence from the group: H and C.sub.1 -C.sub.3 alkyl. 27. A method according to claim 26, wherein: C.sub.h is ##STR162## A.sup.1 is selected from the group: OH, and a bond to L.sub.n ; A.sup.2, A.sup.4, and A.sup.6 are each N; A.sup.3, A.sup.5, and A.sup.8 are each OH; A.sup.7 is a bond to L.sub.n or NH-bond to L.sub.n ; E is a C.sub.2 alkyl substituted with 0-1 R.sup.17 ; R.sup.17 is .dbd.O; alternatively, C.sub.h is ##STR163## A.sup.1 is selected from the group: OH, and a bond to L.sub.n ; A.sup.2, A.sup.3 and A.sup.4 are each N; A.sup.5, A.sup.6 and A.sup.8 are each OH; A.sup.7 is a bond to L.sub.n ; E is a C.sub.2 alkyl substituted with 0-1 R.sup.17 ; R.sup.17 is .dbd.O; alternatively, C.sub.h is ##STR164## A.sup.1 is NH.sub.2 or N.dbd.C(R.sup.20)(R.sup.21); E is a bond; A.sup.2 is NHR.sup.13 ; R.sup.13 is a heterocycle substituted with R.sup.17, the heterocycle being selected from pyridine and pyrimidine; R.sup.17 is selected from a bond to L.sub.n, C(.dbd.O)NHR.sup.18 and C(.dbd.O)R.sup.18 ; R.sup.18 is a bond to L.sub.n ; R.sup.24 is selected from the group: --CO.sub.2 R.sup.25, --OR.sup.25, --SO.sub.3 H, and --N(R.sup.25).sub.2 ; and, R.sup.25 is independently selected at each occurrence from the group: hydrogen and methyl. 28. A method according to claim 11, wherein the compound is selected from the group consisting of: (S,S,S)-4-(N-(3-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoy l)-5-(carboxymethyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl) -4-(4-carboxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclodecyl )acetylamino)butanoyl amino)butanoic acid; (S)-2-(2,5-diaza-5-(6((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))c arbonylamino)hexyl)-9-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-4-oxo bicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid; (S)-2-(2,5-diaza-9-(N-(6-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridy l))carbonylamino)hexyl)-N-(benzimidazol-2-ylmethyl)carbamoyl)-5-methyl-4-ox obicyclo[5.4.0]undeca-1(7),8,10-trien-3-yl)acetic acid; (S,S)-2-(2-aza-2-((5-(N-(1,3-bis(N-(6-(aminohexyl-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)acetic acid)(2-(2,5-diaza-9-(N-(benzimidazol-2-ylmethyl)propyl)carbamoyl)(2-pyrid yl))amino)vinyl)benzenesulfonic acid; (S,S,S)-4-(N-(3-(3,6-diaza-5-(carboxymethyl)-10-(N-(imidazol-2-ylmethyl)-N- benzylcarbamoyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-4-(4-carboxy-2-(2-(1,4,7,1 0-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)acetylamino)butanoylamino )butanoic acid; (S,S)-3-(N-(3-(3,6-diaza-5-(carboxymethyl)-10-(N-(imidazol-2-ylmethyl)-N-be nzylcarbamoyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-3-(2-(1,4,7,10-tetraaza-4, 7,10-tris (carboxymethyl)cyclododecyl)acetylamino)propanoic acid; (S,S,S,S,S,S,S,S)-4-(N-1,3-bis(N-3-carboxy-1-(N-(3-(3,6-diaza-10-(N-(benzim idazol-2-ylmethyl)-N-methylcarbamoyl)-5-(carboxymethyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-4,4-dihydroxypentyl)carbam oyl)propyl)carbamoyl)-4-(5,5-dihydroxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris( carboxymethyl)cyclodecyl)acetylamino)butanoic acid; (S,S,S,S,S,S,S,S,S,S)-2-(4-(N-(1,3-bis(N-(3-(N-(3-(3,6-diaza-10-(N-(benzimi dazol-2-ylmethyl)-N-methylcarbamoyl)-5-((methoxycarbonyl)methyl)-4-oxobicyc lo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)-1-(methoxycarbonyl)propyl) carbamoyl)propyl)carbamoyl)propyl)carbamoyl)-4-(2-(2-(1,4,7,10-tetraaza-4,7 ,10-tris(carboxymethyl)cyclodecyl)acetylamino)-4-carboxybutanoylamino)-4-ca rboxybutanoylamino)butanoylamino)-4-(N-(3-(3,6-diaza-10-(N-(benzimidazol-2- ylmethyl)-N-methyl carbamoyl)-5-((methoxycarbonyl)methyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propyl)carbamoyl)butanoic acid; (S)-2-(2,5-diaza-5-(3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino) (3-pyridyl))carbonylamino)propoxy)ethoxy)ethoxy)propyl)-9-(N-(benzimidazol -2-ylmethyl)-N-methylcarbamoyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)acetic acid; (S,S,S,S,S)-4-(N-(1,3-bis(N-(3-(2-(2-(3-(3,6-diaza-10-(N-(benzimidazol-2-yl methyl)-N-methylcarbamoyl) -5-(carboxymethyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propy l)carbamoyl)-4-(5,5-dihydroxy-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxyme thyl)cyclododecyl)acetylamino)hexanoylamino)butanoic acid; (S,S,S)-2-(2,5-diaza-9-(N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl)-4-ox o-5-(6-(4-(N-((R,S,S,S)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl)-2-(4-(N-((R, S,S,S)-2,3,4,5,6-pentahydroxy hexyl)carbamoyl)-2-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclode cyl)acetylamino)butanoylamino)butanoylamino)hexyl)bicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)acetic acid; (S,S,S,S)-2-(4-(N-(1-(N-(1-(N-(6-(3,6-diaza-10-(N-(benzimidazol-2-ylmethyl) -N-methylcarbamoyl)-5-(carboxymethyl)-4-oxobicyclo[5.4. 0]undeca-1(7),8,10-trien-3-yl)hexyl)carbamoyl)-3-(N-cyclo(Lys-Arg(Mtr)-Gly -Asp(OtBu)-D-Phe}[ganmma-LysNH]carbamoyl)propyl)carbamoyl)-3-carboxypropyl) carbamoyl)-4-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl)a cetylamino)butanoic acid; 4-[N-(3-{(2R)-7-[N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl]-2-(carboxym ethyl)-3-oxo(1H, 2H,5H-benzo[f]1,4-diazepin-4-yl)}propyl)carbamoyl](4S)-4-[(4S)-4-(N-{(1S)- l-[N-(3-{(2S)-7-[N-(benzimidazol-2-ylmethyl)-N-methylcarbamoyl]-2-(carboxym ethyl)-3-oxo (1H,2H,5H-benzo[f]1,4-diazepin-4-yl)}propyl)carbamoyl]-3-carboxypropyl}car bamoyl)-4-{2-[1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecyl]acet ylamino)butanoylamino]butanoic acid; 2-(4-{3-[(6-([(1E)-1-aza-2-(2-sulfophenyl)vinyl]amino)(3-pyridyl))carbonyla mino]propyl}(2S)-7-{N-[2-(amidinoamino)ethyl]-N-methylcarbamoyl}-3-oxo-1H,2 H,5H-benzo[f]1,4-diazepin-2-yl)acetic acid; and 2-[9-(N-{6-[(6-([(1E)-1-aza-2-(2-sulfophenyl)vinyl]amino}(3-pyridyl))carbon ylamino]hexyl}-N-(benzimidazol-2-ylmethyl)carbamoyl)(5S)-5,6,11-trihydrodib enzo[b,e][7]annulen-5-yl]acetic acid; or a pharmaceutically acceptable salt form thereof.

Details for Patent 6,569,402

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eisai, Incorporated	ONTAK	denileukin diftitox	Injection	103767	02/05/1999		2018-12-18