US 6,548,663 B1 · Benzodiazepine vitronectin receptor antagonist pharmaceuticals

Abstract

The present invention describes novel compounds of the formula: (Q)d—Ln—Ch, 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 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.

A method of imaging formation of new blood vessels in a patient comprising:

(1) administering a diagnostically effective amount of a diagnostic radiopharmaceutical, a MRI contrast agent, or a X-ray contrast agent to a patient by injection or infusion;
and
(2) imaging the area of the patient wherein the desired formation of new blood vessels is located,
wherein the diagnostic radiopharmaceutical, MRI contrast agent, or X-ray contrast agent comprises:
i) a radioisotope selected from the group consisting of:
99mTc, 95Tc, 111In, 62Cu, 64Cu, 67Ga, or a paramagnetic metal ion, selected from the group consisting of:
Gd(III), Dy(III), Fe(III), and Mn(II), or a metal selected from the group:
Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag, and Ir;
and
ii) a compound of the formula:
(Q)d—Ln—Ch or (Q)d—Ln—(Ch)d′
wherein, Q is a compound of Formula (I):
wherein:
one of R or R1 is selected from a bond to Ln or (CH2)1-4 or an NH bond to Ln and the other of R or R1 is selected from C1-4 alkyl, benzyl or phenethyl;
R2 is selected from benzimidazole or imidazole;
R3 is selected from H, C1-4 alkyl or benzyl;
R4 is selected from H, C1-4 alkyl or benzyl;
d is selected from 1, 2 and 3;
Ln is a linking group having the formula:
(CR6R7)g—(W)h—(CR6aR7a)g′—(Z)k—(W)h′—(CR8R9)g″—(W)h″—(CR8aR9a)g′″—(W)h′″—(CR8bR9b)g″″
provided that g+h+g′+k+h′+g″+h″+g′″ is other than 0;
W is independently selected at each occurrence from the group:
O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO2, (OCH2CH2)s, (CH2CH20)s′, (OCH2CH2CH2)s″, (CH2CH2CH2O)t, and (aa)t′;
aa is independently at each occurrence an amino acid;
Z is selected from the group:
aryl substitued with 0-3 R10, C3-10 cycloalkyl substituted with 0-3 R10, and a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R10;
R6, R6a, R7, R7a, R8, R8a, R8b, R9, R9a and R9b are independently selected at each occurrence from the group:
H, ═O, COOH, SO3H, PO3H, C1-C5alkyl substituted with 0-3 R10, aryl substituted with 0-3 R10, benzyl substituted with G-3 R10, and C1-C5 alkoxy substituted with 0-3 R10, NHC(═O)R11, C(═O)NHR11, NHC(═O)NHR11, NHR11, R11, and a bond to Ch;
R10 is independently selected at each occurrence from the group:
a bond to Ch COOR11, OH, NHR11, C(═O)NHR11, NH(C═O)R11,SO3H, PO3H, ═O, R11, aryl substituted with 0-3 R11, C1-5 alkyl substituted with 0-1 R12, C1-5 alkoxy substituted with 0-1 R12, and a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R11;
R11 is independently selected at each occurrence from the group:
H, C1-C10 alkyl substituted with 0-1 R12, aryl substituted with 0-1 R12, a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R12, C3-10 cycloalkyl substituted with 0-1 R12, polyalkylene glycol substituted with 0-1 R12, carbohydrate substituted with 0-1 R12, cyclodextrin substituted with 0-1 R12, amino acid substituted with 0-1 R12 polycarboxyalkyl substituted with 0-1 R12 polyazaalkyl substituted with 0-1 R12, peptide substituted with 0-1 R12, wherein the peptide is comprised of 2-10 amino acids, and a bond to Ch;
R12 is a bond to Ch;
k is selected from 0, 1, and 2;
h is selected from 0, 1, and 2;
h′ is selected from 0, 1, 2, 3, 4, and 5;
h″ is selected from 0, 1, 2, 3, 4, and 5;
h′″ is selected from 0, 1, 2, 3, 4, and 5;
g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
g″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
g′″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
g″″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
Ch is a metal bonding unit having a formula selected from the group:
A1, A2, A3, A4, A5, A6, A7, and A8 are independently selected at each occurrence from the group:
NR13, NR13R14, S, SH, S(Pg), O, OH, PR13, PR13R14, P(O)R15R16, CO2H and a bond to Ln;
E is a bond, CH, or a spacer group independently selected at each occurrence from the group:
C1-C10 alkyl substituted with 0-3 R17, aryl substituted with 0-3 R17, C3-10 cycloalkyl substituted with 0-3 R17, heterocyclo-C1-10 alkyl substituted with 0-3 R17, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O, C6-10 aryl-C1-10 alkyl substituted with 0-3 R17, C1-10 alkyl-C6-10 aryl-substituted with 0-3 R17, and a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R17;
R13 and R14 are each independently selected from the group:
a bond to Ln, hydrogen, C1-C10 alkyl substituted with 0-3 R17, aryl substituted with 0-3 R17, C1-10 cycloalkyl substituted with 0-3 R17, heterocyclo-C1-10 alkyl substituted with 0-3 R17, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O, C6-10 aryl-C1-10 alkyl substituted with 0-3 R17, C1-10 alkyl-C6-10 aryl-substituted with 0-3 R17, a 5-10 membered heterocyclic ring system having 14 heteroatoms independently selected from N, S, and O and substituted with 0-3 R17, and an electron, provided that when one of R13 or R14 is an electron, then the other is also an electron;
alternatively, R13 and R14 combine to form ═C(R20)(R21);
R15 and R16 are each independently selected from the group:
a bond to Ln, —OH, C1-C10 alkyl substituted with 0-3 R17, C1-C10 alkyl substituted with 0-3 R17, aryl substituted with 0-3 R17, C1-10 cycloalkyl substituted with 0-3 R17, heterocyclo-C1-10 alkyl substituted with 0-3 R17, wherein the heterocyclo group is a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O, C6-10 aryl-C1-10 alkyl substituted with 0-3 R17, C1-10 alkyl-C6-10 aryl-substituted with 0-3 R17, and a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R17;
R17 is independently selected at each occurrence from the group:
a bond to Ln, ═O, F, Cl, Br, I, —CF3, —CN, —CO2R18, —C(═O)R18, —C(═O)N(R18)2, —CHO, —CH2OR18, —OC(═O)R18, —OC(═O)OR18a, —OR18, —OC(═O)N(R18)2, —NR19C(═O)R18, —NR19C(═O)OR18a, —NR19C(═O)N(R18)2, —NR19SO2N(R18)2, —NR19SO2R18a, —SO3H, —SO2R18a, —SR18, —S(═O)R18a, —SO2N(R18)2, —N(R18)2, —NHC(═S)NHR18, ═NOR18, NO2, —C(═O)NHOR18, —C(═O)NHNR18R18a, —OCH2CO2H, 2-(1-morpholino)ethoxy, C1-C5 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C2-C6 alkoxyalkyl, aryl substituted with 0-2 R18, and a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O;
R18, R18a, and R19 are independently selected at each occurrence from the group:
a bond to Ln, H, C1-C6 alkyl, phenyl, benzyl, C1-C6 alkoxy, halide, nitro, cyano, and trifluoromethyl;
Pg is a thiol protecting group;
R20 and R21 are independently selected from the group:
H, C1-C10 alkyl, —CN, —CO2R25, —C(═O)R25, —C(═O)N(R25)2, C2-C10 1-alkene substituted with 0-3 R23, C2-C10 1-alkyne substituted with 0-3 R23, aryl substituted with 0-3 R23, unsaturated 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R23, and unsaturated C3-10 carbocycle substituted with 0-3 R23;
alternatively, R20 and R21, taken together with the divalent carbon radical to which they are attached form:
R22 and R23 are independently selected from the group:
H, R24, C1-C10 alkyl substituted with 0-3 R24, C2-C10 alkenyl substituted with 0-3 R24, C2-C10 alkynyl substituted with 0-3 R24, aryl substituted with 0-3 R24, a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R24, and C3-10 carbocycle substituted with 0-3 R24;
alternatively, R22, R23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O;
a and b indicate the positions of optional double bonds and n is 0 or 1;
R24 is independently selected at each occurrence from the group:
═O, F, Cl, Br, I, —CF3, —CN, —CO2R25, —C(═O)R25, —C(═O)N(R25)2, —N(R25)3+, —CH20R25, —OC(═O)R25, —OC(═O)OR25a, —OR25, —OC(═O)N(R25)2, —NR26C(═O)R25, —NR26C(═O)OR25a, —NR26C(═O)N(R25)2, —NR26SO2N(R25)2, —NR26SO2R25a, —SO3H, —SO2R25a, —SR25, —S(═O)R25a, —SO2N(R25)2, —N(R25)2, ═NOR25, —C(═O)NHOR25, —OCH2CO2H, and 2-(1-morpholino)ethoxy;
and,
R25, R25a, and R26 are each independently selected at each occurrence from the group:
hydrogen and C1-C6 alkyl;
and a pharmaceutically acceptable salt thereof.

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Benzodiazepine vitronectin receptor antagonist pharmaceuticals

Life of this patent

Benzodiazepine vitronectin receptor antagonist pharmaceuticals

Life of this patent

Abstract

Claims4