US2008193380A1PendingUtilityA1
Radiolabeled selective androgen receptor modulators and their use in prostate cancer imaging and therapy
Est. expiryFeb 28, 2022(expired)· nominal 20-yr term from priority
A61K 51/04A61K 51/0406A61K 51/0402A61K 51/0446A61K 51/0459A61K 51/0455
67
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Claims
Abstract
Provided is a class of radiolabeled androgen receptor targeting agents (ARTA), useful for prostate cancer imaging and in treating or preventing prostate cancer. The agents define a new subclass of radiolabeled compounds, which are selective androgen receptor modulators (SARM), which demonstrate antiandrogenic activity of a nonsteroidal ligand for the androgen receptor, and/or which bind irreversibly to the androgen receptor. The present invention further provides methods for a) imaging of cancer in a subject, b) imaging an androgen receptor-containing tissue in a subject, c) in-vivo imaging in a subject, d) treating a subject suffering from prostate cancer, e) delaying the progression of prostate cancer in a subject suffering from prostate cancer, f) preventing the recurrence of prostate cancer in a subject suffering from prostate cancer, and g) treating the recurrence of prostate cancer in a subject suffering from prostate cancer, which comprise using the radiolabeled compounds of the present invention. The present invention further provides a method of producing the radiolabeled SARM compounds, and precursor compounds useful in the preparation of the radiolabeled SARM compounds.
Claims
exact text as granted — not AI-modified1 . A method for imaging of cancer in a subject, comprising the steps of:
contacting an androgen receptor of said subject with a radiolabeled compound, under conditions effective to bind said radiolabeled compound to said androgen receptor; and detecting the presence of said radiolabeled compound bound to said androgen receptor, wherein said compound is represented by the compound of formula I:
wherein
X is a radioactive or nonradioactive. O, S, SO, CH, NH, NR, Se, PR, or NO, or X is a bond;
G is a radioactive or nonradioactive O or S;
T is a radioactive or nonradioactive OH, OR, —NHCOCH 3 , or NHCOR;
Z is a radioactive or a nonradioactive NO, CN, COR, COOH, or CONHR;
Y is a radioactive or a nonradioactive CF 3 , F, Br, Cl, I, CN; or Sn(R) 3 ;
Q is a radioactive or a nonradioactive alkyl, halogen, CF 3 , CN, C(R) 3 , Sn(R) 3 . N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR. NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 . NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is a radioactive or a nonradioactive alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is a radioactive or nonradioactive CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
R 2 is a radioactive or a nonradioactive F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR; and R 3 is a radioactive or a nonradioactive F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 or Sn(R) 3 .
2 . The method of claim 1 , wherein said cancer is prostate cancer.
3 . A method of in-vivo imaging in a subject, comprising the steps of:
administering to said subject a pharmaceutical composition comprising a radiolabeled compound and detecting the presence of said radiolabeled compound in said subject, wherein said compound is represented by the structure of formula I:
wherein
X is a radioactive or nonradioactive, O, S, SO 2 , CH 2 , NH, NR, Se, PR, or NO, or X is a bond;
G is a radioactive or nonradioactive O or S;
T is a radioactive or nonradioactive OH, OR, —NHCOCH 3 , or NHCOR;
Z is a radioactive or a nonradioactive NO 2 , CN, COR, COOH, or CONHR;
Y is a radioactive or a nonradioactive CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
Q is a radioactive or a nonradioactive alkyl, halogen, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is a radioactive or a nonradioactive alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is a radioactive or nonradioactive CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
R 2 is a radioactive or a nonradioactive F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R), SR; and R 3 is a radioactive or a nonradioactive F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 or Sn(R) 3 .
4 . A method of treating a subject suffering from prostate cancer, said method comprising the steps of administering to said subject a pharmaceutical composition comprising the radiolabeled compound, in an amount effective to treat prostate cancer in said subject, wherein said compound is represented by the structure of formula I:
wherein
X is a radioactive or nonradioactive, O, S, SO 2 , CH 2 , NH, NR, Se, PR, or NO, or X is a bond;
G is a radioactive or nonradioactive O or S;
T is a radioactive or nonradioactive OH, OR, —NHCOCH 3 , or NHCOR;
Z is a radioactive or a nonradioactive NO 2 , CN, COR, COOH, or CONHR;
Y is a radioactive or a nonradioactive CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
Q is a radioactive or a nonradioactive alkyl, halogen, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 . NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is a radioactive or a nonradioactive alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is a radioactive or nonradioactive CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
R 2 is a radioactive or a nonradioactive F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR; and R 3 is a radioactive or a nonradioactive F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 or Sn(R) 3 .
5 . The method according to claim 4 , further comprising the step of administering to said subject a chemotherapeutic agent, a radiosensitizer agent, or a combination thereof.
6 . A method of delaying the progression of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject a pharmaceutical composition comprising the radiolabeled compound, in an amount effective to delay the progression of prostate cancer in said subject, wherein said compound is represented by the structure of formula I:
wherein
X is a radioactive or nonradioactive. O, S, SO 2 , CH 2 , NH, NR, Se, PR, or NO, or X is a bond;
G is a radioactive or nonradioactive O or S;
T is a radioactive or nonradioactive OH, OR, —NHCOCH 3 , or NHCOR;
Z is a radioactive or a nonradioactive NO 2 , CN, COR, COOH, or CONHR;
Y is a radioactive or a nonradioactive CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
Q is a radioactive or a nonradioactive alkyl, halogen, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR. NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is a radioactive or a nonradioactive alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is a radioactive or nonradioactive CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
R 2 is a radioactive or a nonradioactive F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR; and R 3 is a radioactive or a nonradioactive F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 or Sn(R) 3 .
7 . The method according to claim 6 , further comprising the step of administering to said subject a chemotherapeutic agent, a radiosensitizer agent, or a combination thereof.
8 . A method of preventing the recurrence of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject a pharmaceutical composition comprising the radiolabeled compound, in an amount effective to prevent the recurrence of prostate cancer in said subject, wherein said compound is represented by the structure of formula I:
wherein
X is a radioactive or nonradioactive, O, S, SO 2 , CH 2 , NH, NR, Se, PR, or NO, or X is a bond;
G is a radioactive or nonradioactive O or S;
T is a radioactive or nonradioactive OH, OR, —NHCOCH 3 , or NHCOR;
Z is a radioactive or a nonradioactive NO 2 , CN, COR, COOH, or CONHR;
Y is a radioactive or a nonradioactive CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
Q is a radioactive or a nonradioactive alkyl, halogen, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is a radioactive or a nonradioactive alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is a radioactive or nonradioactive CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 .
R 2 is a radioactive or a nonradioactive F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR; and R 3 is a radioactive or a nonradioactive F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 or Sn(R) 3 .
9 . The method according to claim 8 , further comprising the step of administering to said subject a chemotherapeutic agent, a radiosensitizer agent, or a combination thereof.
10 . A method of treating the recurrence of prostate cancer in a subject suffering from prostate cancer, comprising the step of adniinistering to said subject a pharmaceutical composition comprising the radiolabeled compound, in an amount effective to treat the recurrence of prostate cancer in said subject, wherein said compound is represented by the structure of formula I:
wherein
X is a radioactive or nonradioactive, O, S, SO, CH, NH, NR, Se, PR, or NO, or X is a bond;
G is a radioactive or nonradioactive O or S;
T is a radioactive or nonradioactive OH, OR, —NHCOCH 3 , or NHCOR;
Z is a radioactive or a nonradioactive NO 2 , CN, COR, COOH, or CONHR;
Y is a radioactive or a nonradioactive CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
Q is a radioactive or a nonradioactive alkyl, halogen, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is a radioactive or a nonradioactive alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is a radioactive or nonradioactive CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
R 2 is a radioactive or a nonradioactive F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR; and R 3 is a radioactive or a nonradioactive F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 or Sn(R) 3 .
11 . The method according to claim 10 , further comprising the step of administering to said subject a chemotherapeutic agent, a radiosensitizer agent, or a combination thereof.
12 . A radiolabeled compound represented by the structure of formula II:
RI—(Ch) n -(Li) m -(SARM) II wherein RI is a radioisotope; Ch is a metal chelator; Li is a linker moiety; m is 0 or 1; n is 0 or 1; and
SARM is a selective androgen receptor modulator compound represented by the structure of any of formulas III-VI:
Formula III:
wherein G is O or S;
X is a bond, O, S, SO 2 , CH 2 , NH, NR, Se, PR, or NO;
T is OH, OR, —NHCOCH 3 , or NHCOR
Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
Y is CF 3 , F, I, Br, Cl, CN, C(R) 3 or Sn(R) 3 ;
Q is alkyl, halogen, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate or any combination thereof;
Formula IV:
wherein X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
G is O or S;
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
T is OH, OR, —NHCOCH 3 , or NHCOR;
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF, aryl, phenyl, halgoen, alkenyl or OH:
A is a ring selected from:
B is a ring selected from:
wherein
A and B cannot simultaneously be a benzene ring;
Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
Y is CF 3 , F, I, Br, Cl, CN, C(R) 3 or Sn(R) 3 ;
Q 1 and Q 2 are independently of each other a hydrogen, alkyl, halogen, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO
Q 3 and Q 4 are independently of each other a hydrogen, alkyl, halogen, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R SR, SCN, NCS, OCN, or NCO;
W is O, NH, NR, NO or S; and
W 2 is N or NO;
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate or any combination thereof;
Formula V:
wherein
X is a bond, O, S, SO 2 , CH 2 , NH, NR, Se, PR, or NO
G is O or S;
T is OH, OR, —NHCOCH 3 , or NHCOR;
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH;
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
R 2 is F, Cl, Br, I, CH 3 , CF 3 , OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR;
R 3 is F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , Sn(R) 3 , or R 3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
Z is NO 2 , CN, COR, COOH, or CONHR;
Y is CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
Q is H, alkyl, halogen, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OH, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
n is an integer of 1-4; and
m is an integer of 1-3;
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate or any combination thereof; or
Formula VI:
wherein
X is a bond, O, S, SO 2 , CH 2 , NH, NR, Se, PR, or NO;
G is O or S;
Z is NO 2 , CN, COR, COOH, or CONHR;
Y is CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
Q is N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
And
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH.
or its isomer, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate or any combination thereof The radiolabeled compound of claim 12 wherein RI is a metallic radionuclide.
13 . The radiolabeled compound of claim 12 , wherein RI is a non-metallic radionuclide.
14 . The radiolabeled compound of claim 12 , wherein RI is 99 Tc, 131 I, 125 I, 123 I, 117 Sn, 111 In, 97 Ru, 203 Pb, 67 Ga, 68 Ga, 89 Zr 90 Y, 177 Lu, 149 Pm, 153 Sm, 166 Ho, 131 I, 32 P, 211 At, 47 Sc, 109 Pd, 105 Rh, 186 Re, 188 Re, 60 Cu, 62 Cu, 64 Cu, or 67 Cu.
15 . The radiolabeled compound of claim 12 , wherein RI is 99 Tc.
16 . The radiolabeled compound of claim 12 , wherein Li is a hydrocarbon chain, a carbohydrate, a cyclodextrin, an amino acid, a peptide, a polyalkylene glycol, or any combination thereof.
17 . The radiolabeled compound of claim 12 , wherein Ch is a diaminedithiol, a monoamine-monoamide-dithiol, a triamide-monothiol, a monoamine-diamide-monothiol, a diaminedioxime, a cyclic or acyclic polyaminocarboxylate, or a hydrazine.
18 . The radiolabeled compound according to claim 12 , wherein said SARM compound is represented by the structure of formula III.
19 . The radiolabeled compound according to claim 18 , wherein G is O, X is O, T is OH, Y is CF and R 1 is CH 3 .
20 . (canceled)
21 . (canceled)
22 . (canceled)
23 . The radiolabeled compound according to claim 19 , wherein Z is NO 2 or CN.
24 . (canceled)
25 . (canceled)
26 . The radiolabeled compound according to claim 19 , wherein Q is NHCOCH 3 , F or NCS.
27 . (canceled)
28 . (canceled)
29 . The radiolabeled compound according to claim 12 , wherein said SARM compound is represented by the structure of formula IV.
30 . The radiolabeled compound according to claim 29 , wherein G is O, X is O, T is OH, R 1 is CH 3 and Y is CF 3 .
31 . (canceled)
32 . (canceled)
33 . (canceled)
34 . The radiolabeled compound according to claim 30 , wherein Z is NO 2 or CN.
35 . (canceled)
36 . (canceled)
37 . The radiolabeled compound according to claim 30 , wherein Q 1 is NHCOCH 3 , F or NCS.
38 . (canceled)
39 . (canceled)
40 . The radiolabeled compound according to claim 12 , wherein said SARM compound is represented by the structure of formula V.
41 . The radiolabeled compound according to claim 40 , wherein G is O, X is O, T is OH, R 1 is CH 3 , and Y is CF 3 .
42 . (canceled)
43 . (canceled)
44 . (canceled)
45 . The radiolabeled compound according to claim 41 , wherein Z is NO 2 or CN.
46 . (canceled)
47 . (canceled)
48 . The radiolabeled compound according to claim 41 , wherein Q is NHCOCH 3 , F or NCS.
49 . (canceled)
50 . (canceled)
51 . The radiolabeled compound according to claim 12 , wherein said SARM compound is represented by the structure of formula VI.
52 . The radiolabeled compound according to claim 51 , wherein X is O and Y is CF 3 .
53 . The radiolabeled compound according to claim 52 , wherein Z is NO 2 or CN.
54 . (canceled)
55 . (canceled)
56 . The radiolabeled compound according to claim 52 , wherein Q is NHCOCH 3 , F or NCS.
57 . (canceled)
58 . (canceled)
59 . A composition comprising the radiolabeled compound of claim 12 , and a pharmaceutically acceptable carrier.
60 . A pharmaceutical composition for use in medical therapy comprising the radiolabeled compound of claim 12 , and a pharmaceutically acceptable carrier.
61 . A pharmaceutical composition for use in medical diagnosis comprising the radiolabeled compound of claim 12 , and a pharmaceutically acceptable carrier.
62 . A method for imaging of cancer in a subject, comprising the steps of:
contacting an androgen receptor of said subject with a radiolabeled compound according to claim 12 , under conditions effective to bind said radiolabeled compound to said androgen receptor; and detecting the presence of said radiolabeled compound bound to said androgen receptor.
63 . The method of claim 63 , wherein said cancer is prostate cancer.
64 . A method of in-vivo imaging in a subject, comprising the steps of:
administering to said subject a pharmaceutical composition comprising a radiolabeled compound according to claim 12 ; and detecting the presence of said radiolabeled compound in said subject.
65 . A method of treating a subject suffering from prostate cancer, said method comprising the steps of administering to said subject a pharmaceutical composition comprising the radiolabeled compound according to claim 12 , in an amount effective to treat prostate cancer in said subject.
66 . The method according to claim 66 , further comprising the step of administering to said subject a chemotherapeutic agent, a radiosensitizer agent, or a combination thereof.
67 . A method of delaying the progression of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject a pharmaceutical composition comprising the radiolabeled compound according to claim 12 , in an amount effective to delay the progression of prostate cancer in said subject.
68 . The method according to claim 68 , further comprising the step of administering to said subject a chemotherapeutic agent, a radiosensitizer agent, or a combination thereof.
69 . A method of preventing the recurrence of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject a pharmaceutical composition comprising the radiolabeled compound according to claim 12 , in an amount effective to prevent the recurrence of prostate cancer in said subject.
70 . The method according to claim 70 , further comprising the step of administering to said subject a chemotherapeutic agent, a radiosensitizer agent, or a combination thereof.
71 . A method of treating the recurrence of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject a pharmaceutical composition comprising the radiolabeled compound according to claim 12 , in an amount effective to treat the recurrence of prostate cancer in said subject.
72 . The method according to claim 72 , further comprising the step of administering to said subject a chemotherapeutic agent, a radiosensitizer agent, or a combination thereof.
73 . A method of producing a radiolabeled selective androgen receptor modulator (SARM) compound of formula I, comprising:
providing a precursor compound represented by the structure of formula VII:
wherein
X is a bond, O, S, SO 2 , CH 2 , NH, NR, Se, PR, or NO;
G is O or S;
T is OH, OR, —NHCOCH 3 , or NHCOR;
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH;
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
Z 1 is a NO 2 , CN, COR, COOH, or CONHR:
Y 1 is CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
R 33 is F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR; or
Z 1 , Y 1 and R 33 are independently of each other an isothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, a-chloroethylamine, a diazonium salt, a triazene group, a tertiary alkyl group, an oxy group, an alkoxy group, a stannoalkyl group, a stannoaryl group, an unsubstituted or substituted boronic acid, an alkyl silane group, a pentafluorosilicate group, an alkylgermano group, a halomercury group, a trifluoroacetylthallate group, or a thallium difluoride group;
Q 1 is CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR. CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R 22 is nonradioactive F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR; or
Q 1 and R 22 are independently of each other a diazonium salt, a triazene group, a tertiary alkyl amino group, a nitro group, an oxy or an alkoxy group, an amino or an alkylamino group, a stannoalkyl group (SnAlk 3 ), a stannoaryl group (SnAr 3 ), an unsubstituted or a substituted boronic acid, an alkyl silane group (SiR 3 ), a pentafluorosilicate (SiF 5 ) group, an alkylgermano group (GeAlk 2 ), a halomercury group (HgHal), a trifluoroacetyl thallate croup, or a thallium difluoride group;
providing, a radioactive compound; and
reacting the precursor compound and the radioactive compound under conditions effective to produce a radiolabeled selective androgen receptor modulator (SARM) compound represented by the structure of formula I:
wherein X is a radioactive or nonradioactive O, S, SO 2 , CH 2 , NH, NR, Se, PR, or NO, or X is a bond;
G is a radioactive or nonradioactive O or S;
T is a radioactive or nonradioactive OH, OR, —NHCOCH 3 , or NHCOR;
Z is a radioactive or a nonradioactive NO 2 , CN. COR, COOH, or CONHR;
Y is a radioactive or a nonradioactive CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
Q is a radioactive or a nonradioactive alkyl, halogen, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is a radioactive or a nonradioactive alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is a radioactive or nonradioactive CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
R 2 is a radioactive or a nonradioactive F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR; and
R 3 is a radioactive or a nonradioactive F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , Sn(R) 3 ;
wherein at least one of X, T, Z, Y, Q, R, R 1 , R 2 or R 3 is radioactive,
or its isomer, pharmaceutically acceptable salt, N-oxide, hydrate or any combination thereof.
74 . The method of claim 74 , wherein Y 1 is a stannoalkyl.
75 . The method of claim 74 , wherein Y 1 is Sn(CH 3 ) 3 .
76 . The method of claim 74 , wherein Y is a radioactive halogen.
77 . A precursor compound useful in producing a radiolabeled selective androgen receptor modulator (SARM) compound, said precursor compound represented by the structure of formula VII:
wherein
X is a bond, O, S, SO 2 , CH 2 , NH, NR, Se, PR, or NO;
G is O or S;
T is OH, OR, —NHCOCH 3 , or NHCOR;
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 ,
CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH;
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
Z 1 is a NO 2 , CN, COR, COOH, or CONHR;
Y 1 is CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
R 33 is F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR; or
Z 1 , Y 1 and R 33 are independently of each other an isothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, a-chloroethylamine, a diazonium salt, a triazene group, a tertiary alkyl group, an oxy group, an alkoxy group, a stannoalkyl group, a stannoaryl group, an unsubstituted or substituted boronic acid, an alkyl silane group, a pentafluorosilicate group, an alkylgermano group, a halomercury group, a trifluoroacetylthallate group, or a thallium difluoride group;
Q 1 is CF 3 , CN CR 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R 22 is nonradioactive F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , SR; or
Q 1 and R 22 are independently of each other a diazonium salt, a triazene group, a tertiary alkyl amino group, a nitro group, an oxy or an alkoxy group, an amino or an alkylamino group, a stannoalkyl group (SnAlk 3 ), a stannoaryl group (SnAr 3 ), an unsubstituted or a substituted boronic acid, an alkyl silane group (SiR 3 ), a pentafluorosilicate (SiF 5 ) group, an alkylgermano group (GeAlk 2 ), a halomercury group (HgHal), a trifluoroacetyl thallate group, or a thallium difluoride group.
78 . The method of claim 78 , wherein Y 1 is a stannoalkyl.
79 . The method of claim 78 , wherein Y 1 is Sn(CH 3 ) 3 .
80 . The method of claim 78 , wherein Y is a radioactive halogen.
81 . A radiolabeled selective androgen receptor modulator (SARM) compound represented by the structure of formula I:
wherein X is a radioactive or nonradioactive, O, S, SO, CH 2 , NH, NR, Se, PR, or NO, or X is a bond;
G is a radioactive or nonradioactive O or S;
T is a radioactive or nonradioactive OH, OR, —NHCOCH 3 , or NHCOR;
Z is a radioactive or a nonradioactive NO, CN, COR, COOH, or CONHR;
Y is a radioactive or a nonradioactive CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
Q is a radioactive or a nonradioactive alkyl, CF 3 , C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R, SR, SCN, NCS, OCN, NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
R is a radioactive or a nonradioactive alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH;
and
R 1 is a radioactive or nonradioactive CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
R 2 is a radioactive or a nonradioactive F, Cl, Br, I, OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, NR 2 , SR; and
R 3 is a radioactive or a nonradioactive F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , Sn(R) 3 ; or its isomer, pharmaceutically acceptable salt, N-oxide, hydrate or any combination thereof.
82 . The radiolabeled selective androgen receptor modulator compound of claim 82 , wherein R 2 is a radioactive halogen.
83 . The radiolabeled selective androgen receptor modulator compound of claim 82 , wherein R 3 is a radioactive halogen.
84 . The radiolabeled selective androgen receptor modulator compound of claim 82 , wherein said compound is an androgen receptor antagonist.
85 . A composition comprising the radiolabeled compound of claim 82 , and a pharmaceutically acceptable carrier.
86 . A pharmaceutical composition for use in medical therapy comprising the radiolabeled compound of claim 82 , and a pharmaceutically acceptable carrier.
87 . A pharmaceutical composition for use in medical diagnosis comprising the radiolabeled compound of claim 1 , and a pharmaceutically acceptable carrier.
88 . A method for imaging of cancer in a subject, comprising the steps of:
contacting an androgen receptor of said subject with a radiolabeled compound according to claim 82 , under conditions effective to bind said radiolabeled compound to said androgen receptor; and detecting the presence of said radiolabeled compound bound to said androgen receptor.
89 . The method of claim 89 , wherein said cancer is prostate cancer.
90 . A method of in-vivo imaging in a subject, comprising the steps of:
administering to said subject a pharmaceutical composition comprising a radiolabeled compound according to claim 82 ; and detecting the presence of said radiolabeled compound in said subject.
91 . A method of treating a subject suffering from prostate cancer, said method comprising the steps of administering to said subject a pharmaceutical composition comprising the radiolabeled compound according to claim 82 , in an amount effective to treat prostate cancer in said subject.
92 . The method according to claim 92 , further comprising the step of administering to said subject a chemotherapeutic agent, a radiosensitizer agent, or a combination thereof.
93 . A method of delaying the progression of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject a pharmaceutical composition comprising the radiolabeled compound according to claim 82 , in an amount effective to delay the progression of prostate cancer in said subject.
94 . The method according to claim 94 , further comprising the step of administering to said subject a chemotherapeutic agent, a radiosensitizer agent, or a combination thereof.
95 . A method of preventing the recurrence of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject a pharmaceutical composition comprising the radiolabeled compound according to claim 82 , in an amount effective to prevent the recurrence of prostate cancer in said subject.
96 . The method according to claim 96 , further comprising the step of administering to said subject a chemotherapeutic agent, a radiosensitizer agent, or a combination thereof.
97 . A method of treating the recurrence of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject a pharmaceutical composition comprising the radiolabeled compound according to claim 82 , in an amount effective to treat the recurrence of prostate cancer in said subject.
98 . The method according to claim 98 , further comprising the step of administering to said subject a chemotherapeutic agent, a radiosensitizer agent, or a combination thereof.Cited by (0)
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