Patent ID: 6808698
Filing Date: 2004-10-26
Classification: A61K

Abstract:
A method for imaging a pulmonary embolus comprising the steps of:a. localizing a radiolabelled compound at the pulmonary embolus; b. acquiring image slices representing the concentration of radioactivity within the radiolabelled pulmonary embolus; c. assembling the image slices into a three-dimensional matrix of data; d. scanning the three-dimensional matrix of data along an array of parallel lines to determine a maximum value alone each line; and e. assigning the maximum value along each line to a pixel in a two-dimensional array, the position of the pixel corresponding to the position of the line in the array of parallel lines; wherein the localization step comprises the step of localizing a compound of the formula (I), and pharmaceutically acceptable salts thereof, at the pulmonary embolus: |(Q)dâ€²â€”Lnâ€”Châ€²|xâ€”MT(AL1)y(AL2)zâ€ƒâ€ƒ(I), wherein,Q is a glycoprotein IIb/IIIa binding compound; dâ€² is 1-20; Ln is a linking group of formula: M1â€”[Y1(CR55R56)f(Z1)fâ€³Y2]fâ€²â€”M2, wherein:M1 is â€”[(CH2)gZ1]gâ€²â€”(CR55R56)gâ€³â€”; M2 is â€”(CR55R56)gâ€³â€”[Z1(CH2)g]gâ€²â€”; g is 0; gâ€² is 0; gâ€³ is 0; f is 0; fâ€² is independently 0-10; fâ€³ is independently 0-1; Y1 is a bond; Y2 is NHC(&boxH;O); Z1 is independently selected at each occurrence from a C6-C14 saturated, partially saturated, or aromatic carbocyclic ring system, substituted with 0-4 R57; and a heterocyclic ring system, substituted with 0-4 R57; R55 and R56 are independently selected at each occurrence from: hydrogen; C1-C10 alkyl substituted with 0-5 R57; and alkaryl wherein the aryl is substituted with 0-5 R57; R57 is independently selected at each occurrence from the group: hydrogen, OH, NHR58, C(&boxH;O)R58, OC(&boxH;O)R58, OC(&boxH;O)OR58, C(&boxH;O)OR58, C(&boxH;O)NR58, Câ‰¡N, SR58, SOR58, SO2R58, NHC(&boxH;O)R58, NHC(&boxH;O)NHR58, NHC(&boxH;S)NHR58; or, alternatively, when attached to an additional molecule Q, R57 is independently selected at each occurrence from the group: O, NR58, C&boxH;O, C(&boxH;O)O, OC(&boxH;O)O, C(&boxH;O)Nâ€”, C&boxH;NR58, S, SO, SO2, SO3, NHC(&boxH;O), (NH)2C(&boxH;O), (NH)2C&boxH;S; and, R58 is independently selected at each occurrence from the group: hydrogen; C1-C6 alkyl; benzyl, and phenyl; MT is a transition metal radionuclide; Châ€² is a radionuclide metal chelator or bonding unit bound to the transition metal radionuclide of the formula R40R41Nâ€”N&boxH;; R40 is a heterocycle substituted with 1 R52; R41 is independently selected from the group: hydrogen, aryl substituted with 0-3 R52, C1-C10 alkyl substituted with 0-3 R52, and a heterocycle substituted with 0-3 R52; R52 is a bond to Ln; AL1 is a first ligand wherein each of the y first ligands are functionalized aminocarboxylates; AL2 is a second ligand wherein each of the z second ligands are trisubstituted phosphines; x is independently 1-2; y is independently 1-2; z is independently 0-4; and wherein Q is of the formula (II), or a pharmaceutically acceptable salt or prodrug form thereof wherein:R31 is a C6-C14 aromatic carbocyclic ring system substituted with 1 R10; R10 is â€”NR13C(&boxH;O)R13; J is an L-isomer or D-isomer amino acid of structure â€”N(R3)C(R4)(R5)C(&boxH;O)â€”, wherein: R3 is H or C1-C8 alkyl; R4 is H or C1-C3 alkyl; R5 is selected from: hydrogen; C1-C8 alkyl substituted with 0-2 R11; C2-C8 alkenyl substituted with 0-2 R11; C2-C8 alkynyl substituted with 0-2 R11; C3-C10 cycloalkyl substituted with 0-2 R11; aryl substituted with 0-2 R12; a 5-10-membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, or O, said heterocyclic ring being substituted with 0-2 R12; &boxH;O, F, Cl, Br, I, â€”CF3, â€”CN, â€”CO2R13, â€”C(&boxH;O)R13, â€”C(&boxH;O)N(R13)2, â€”CHO, â€”CH2OR13, â€”OC(&boxH;O)R13, â€”OC(&boxH;O)OR13a, â€”OR13, â€”OC(&boxH;O)N(R13)2, â€”NR13C(&boxH;O)R13, â€”NR14C(&boxH;O)OR13a, â€”NR13C(&boxH;O)N(R13)2, â€”NR14SO2N(R13)2, â€”NR14SO2R13a, â€”SO3H, â€”SO2R13a, â€”SR13, â€”S(&boxH;O)R13a, â€”SO2N(R13)2, â€”N(R13)2, â€”NHC(&boxH;NH)NHR13, â€”C(&boxH;NH)NHR13, &boxH;NOR13, NO2, â€”C(&boxH;O)NHOR13, â€”C(&boxH;O)NHNR13R13a, &boxH;NOR13, â€”B(R34)(R35), â€”OCH2CO2H, 2-(1-morpholino)ethoxy, â€”SC(&boxH;NH)NHR13, N3, â€”Si(CH3)3, (C1-C5 alkyl)NHR16; â€”(C0-C6 alkyl)X; where q is independently 0,1; â€”(CH2)mS(O)pâ€²(CH2)2X, where m=1,2 and pâ€²=0-2; and R3 and R4 may also be taken together to form where n=0, 1 and X is R3 and R5 can alternatively be taken together to form â€”(CH2)tâ€” or â€”CH2S(O)pâ€²C(CH3)2â€”, where t=2-4 and pâ€²=0-2; or R4 and R5 can alternatively be taken together to form â€”(CH2)uâ€”, where u=2-5; R16 is selected from: an amine protecting group; 1-2 amino acids; 1-2 amino acids substituted with an amine protecting group; K is a D-isomer or L-isomer amino acid of structure â€”N(R6)CH(R7)C(&boxH;O)â€”, wherein: R6 is H or C1-C8 alkyl; R7 is selected from: â€”(C1-C7 alkyl)X; wherein each q is independently 0-2 and substitution on the phenyl is at the 3 or 4 position; wherein each q is independently 0-2 and substitution on the cyclohexyl is at the 3 or 4 position; â€”(CH2)mOâ€”(C1-C4 alkyl)â€”X, where m=1 or 2; â€”(CH2)mS(O)pâ€²â€”(C1-C4 alkyl)â€”X, where m=1 or 2 and pâ€²=0-2; and X is selected from: â€”N(R13)R13; â€”C(&boxH;NH)(NH2); â€”SC(&boxH;NH)â€”NH2; â€”NHâ€”C(&boxH;NH)(NHCN); â€”NHâ€”C(&boxH;NCN)(NH2); â€”NHâ€”C(&boxH;Nâ€”OR13)(NH2); R6 and R7 can alternatively be taken together to form wherein each q is independently 1 or 2 and whereinn=0 or 1 and X is â€”NH2 or L is â€”Y(CH2)vC(&boxH;O)â€”, wherein Y is NH and v=1 or 2; M is a D-isomer or L-isomer amino acid of structure wherein:qâ€² is 0-2; R17 is H, C1-C3 alkyl; R8 is selected from: â€”CO2R13, â€”SO3R13, â€”SO2NHR14, â€”B(R34)(R35), â€”NHSO2CF3, â€”CONHNHSO2CF3, â€”PO(OR13)2, â€”PO(OR13)R13, â€”SO2NH-heteroaryl (said heteroaryl being 5-10-membered and having 1-4 heteroatoms selected independently from N, S, or O), â€”SO2NH-heteroaryl (said heteroaryl being 5-10-membered and having 1-4 heteroatoms selected independently from N, S, or O), â€”SO2NHCOR13, â€”CONHSO2R13a, â€”CH2CONHSO2R13a, â€”NHSO2NHCOR13a, â€”NHCONHSO2R13a, â€”SO2NHCONHR13; R34 and R35 are independently selected from: â€”OH, â€”F, N(R13)2, or C1-C8-alkoxy; R34 and R35 can alternatively be taken together to form: a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-4 heteroatoms independently selected from N, S, or O; a divalent cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-4 heteroatoms independently selected from N, S, or O; a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-4 heteroatoms independently selected from N, S, or O; R32 is â€”C(&boxH;O)â€”; nâ€³ and nâ€² are independently 0-2; R1 and R22 are independently selected from the following groups: hydrogen, C1-C8 alkyl substituted with 0-2 R11; C2-C8 alkenyl substituted with 0-2 R11; C2-C8 alkynyl substituted with 0-2 R11; C3-C10 cycloalkyl substituted with 0-2 R11; aryl substituted with 0-2 R12; a 5-10-membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring being substituted with 0-2 R12; &boxH;O, F, Cl, Br, I, â€”CF3, â€”CN, â€”CO2R13, â€”C(&boxH;O)R13, â€”C(&boxH;O)N(R13)2, â€”CHO, â€”CH2OR13, â€”OC(&boxH;O)R13, â€”OC(&boxH;O)OR13a, â€”OR13, â€”OC(&boxH;O)N(R13)2, â€”NR13C(&boxH;O)R13, â€”NR14C(&boxH;O)OR13a, â€”NR13C(&boxH;O)N(R13)2, â€”NR14SO2N(R13)2, â€”NR14SO2R13a, â€”SO3H, â€”SO2R13a, â€”SR13, â€”S(&boxH;O)R13a, â€”SO2N(R13)2, â€”N(R13)2, â€”NHC(&boxH;NH)NHR13, â€”C(&boxH;NH)NHR13, &boxH;NOR13, NO2, â€”C(&boxH;O)NHOR13, â€”C(&boxH;O)NHNR13R13a, â€”OCH2CO2H, 2-(1-morpholino)ethoxy; R1 and R21 can alternatively join to form a 3-7 membered carbocyclic ring substituted with 0-2 R12; when nâ€² is 2, R1 or R21 can alternatively be taken together with R1 or R21 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between said carbon atoms; R22 and R23 can alternatively join to form a 3-7 membered carbocyclic ring substituted with 0-2 R12; when nâ€³ is 2, R22 or R23 can alternatively be taken together with R22 or R23 on an adjacent carbon atom to form a direct bond, thereby to form a double or triple bond between the adjacent carbon atoms; R1 and R2, where R21 is H, can alternatively join to form a 5-8 membered carbocyclic ring substituted with 0-2 R12; R11 is selected from one or more of the following: &boxH;O, F, Cl, Br, I, â€”CF3, â€”CN, â€”CO2R13, â€”C(&boxH;O)R13, â€”C(&boxH;O)N(R13)2, â€”CHO, â€”CH2OR13, â€”OC(&boxH;O)R13, â€”OC(&boxH;)OR13a, â€”OR13, â€”OC(&boxH;O)N(R13)2, â€”NR13C(&boxH;O)R13, â€”NR14C(&boxH;O)OR13a, â€”NR13C(&boxH;O)N(R13)2, â€”NR14SO2N(R13)2, â€”NR14SO2R13a, â€”SO3H, â€”SO2R13a, â€”SR13, â€”S(&boxH;O)R13a, â€”SO2N(R13)2, â€”N(R13)2, â€”NHC(&boxH;NH)NHR13, â€”C(&boxH;NH)NHR13, &boxH;NOR13, NO2, â€”C(&boxH;O)NHOR13, â€”C(&boxH;O)NHNR13R13a, â€”OCH2CO2H, 2-(1-morpholino)ethoxy, C1â€”C5 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C2-C6 alkoxyalkyl, C3-C6 cycloalkoxy, C1-C4 alkyl (alkyl being substituted with 1-5 groups selected independently from: â€”NR13R14, â€”CF3, NO2, â€”SO2R13a, or â€”S(&boxH;O)R13a), aryl substituted with 0-2 R12, a 5-10-membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring being substituted with 0-2 R12; R12 is selected from one or more of the following: â€ƒphenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C5 alkoxy, â€”CO2R13, â€”C(&boxH;O)NHOR13a, â€”C(&boxH;O)NHN(R13)2, &boxH;NOR13, â€”B(R34)(R35), C3â€”C6 cycloalkoxy, â€”OC(&boxH;O)R13, â€”C(&boxH;O)R13, â€”OC(&boxH;O)OR13a, â€”OR13, â€”(C1-C4 alkyl)-OR13, â€”N(R13)2, â€”OC(&boxH;O)N(R13)2, â€”NR13C(&boxH;O)R13, â€”NR13C(â‰¡O)OR13a, â€”NR13C(&boxH;O)N(R13)2, â€”NR13SO2N(R13)2, â€”NR13SO2R13a, â€”SO3H, â€”SO2R13a, â€”S(&boxH;O)R13a, â€”SR13, â€”SO2N(R13)2, C2-C6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, â€”OCH2CO2H, 2-(1-morpholino)ethoxy, C1-C4 alkyl (alkyl being substituted with â€”N(R13)2, â€”CF3, NO2, or â€”S(&boxH;O)R13a); â€ƒR13 is selected independently from: H, C1-C10 alkyl, C3-C10 cycloalkyl, C4-C12 alkylcycloalkyl, aryl, â€”(C1-C10 alkyl)aryl, or C3-C10 alkoxyalkyl; â€ƒR13 is C1-C10 alkyl, C3-C10 cycloalkyl, C4-C12 alkylcycloalkyl, aryl, â€”(C1-C10 alkyl)aryl, or C3-C10 alkoxyalkyl; â€ƒwhen two R113 groups are bonded to a single N, said R13 group may alternatively be taken together to form â€”(CH2)2-5â€” or â€”(CH2)O(CH2)â€”; â€ƒR14 is OH, H, C1-C4 alkyl, or benzyl; â€ƒR21 and R23 are independently selected from: â€ƒhydrogen, â€ƒC1-C4 alkyl, optionally substituted with 1-6 halogen; and â€ƒbenzyl; and â€ƒR2 is H or C1-C8 alkyl.