Granted Patent B2

US 9,266,846 · App. 14/474,566 · Granted Feb 23, 2016

Abstract

Claims (67)

1. A method of preparing a compound of Formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

X is N, O, S, or P;

R 1 is hydrogen, alkyl, alkenyl, arylalkyl, alkylarylalkyl, alkoxyalkyl, heteroalkyl, heterocyclylalkyl, or an α-amino protecting group;

R 2 and R 3 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, and carbonyl; or

R 2 or R 3 comprise the following structure,

wherein:

n is 0-6; and

R z is selected from the group consisting of alkyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, and heterocyclyl;

R 4 is alkyl substituted by an amide-linked chelator moiety, alkylaryl substituted by an amide-linked chelator moiety, or alkylarylalkyl substituted by an amide-linked chelator moiety;

wherein R 1 , R 2 , R 3 , and R 4 are each independently unsubstituted or substituted with one or more of the following: alkyl, alkenyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, —NR 19 R 20 , —SH, —S(Pg), —OH, —PR 19 R 20 , P(O)R 21 R 22 , —CO 2 H, ═O, halo, trifluoromethyl, cyano, —CO 2 R 24 , —C(═O)R 24 , —C(═O)N(R 24 ) 2 , —CHO, —CH 2 OR 24 , —OC(═O)R 24 , —OC(═O)OR 24 , —OR 24 , —OC(═O)N(R 24 ) 2 , —NR 24 C(═O)R 24 , —NR 24 C(═O)OR 24 , —NR 24 C(═O)N(R 24 ) 2 , —NR 24 SO 2 N(R 24 ) 2 , —NR 24 SO 2 R 24 , —SO 3 H, —SO 2 R 24 , —SR 24 , —S(═O)R 24 , —SO 2 N(R 24 ) 2 , —N(R 24 ) 2 , —NHC(═S)NHR 24 , ═NOR 24 , NO 2 , —C(═O)NHOR 24 , —C(═O)NHN(R 24 ) 2 , —OCH 2 CO 2 H, 2-(1-morpholino)ethoxy, or a chelator moiety;

R 19 and R 20 are each independently selected from the group consisting of hydrogen, C 1-10 alkyl substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , C 3-10 cycloalkyl substituted with 0-3 R 23 , heterocyclyl-C 1-10 alkyl substituted with 0-3 R 23 , C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 23 , and heterocyclyl substituted with 0-3 R 23 ;

R 21 and R 22 are each independently selected from the group consisting of —OH, C 1-10 alkyl substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , C 3 -10 cycloalkyl substituted with 0-3 R 23 , heterocyclyl-C 1-10 alkyl substituted with 0-3 R 23 , C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 23 , and heterocyclyl substituted with 0-3 R 23 ;

each R 23 is independently selected from the group consisting of ═O, halo, trifluoromethyl, cyano, —CO 2 R 24 , —C(═O)R 24 , —C(═O)N(R 24 ) 2 , —CHO, —CH 2 OR 24 , —OC(═O)R 24 , —OC(═O)OR 24 , —OR 24 , —OC(═O)N(R 24 ) 2 , —NR 24 C(═O)R 24 , —NR 24 C(═O)OR 24 , —NR 24 C(═O)N(R 24 ) 2 , —NR 24 SO 2 N(R 24 ) 2 , —NR 24 SO 2 R 24 , —SO 3 H, —SO 2 R 24 , —SR 24 , —S(═O)R 24 , —SO 2 N(R 24 ) 2 , —N(R 24 ) 2 , —NHC(═S)NHR 24 , ═NOR 24 , —NO 2 , —C(═O)NHOR 24 , —C(═O)NHNR 24 R 24 , —OCH 2 CO 2 H, 2-(1-morpholino)ethoxy, C 1-5 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, C 2-6 alkoxyalkyl, aryl substituted with 0-2 R 24 , and heterocyclyl;

each R 24 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, and carbonyl;

Pg is a thiol protecting group; and

n′ is an integer from 1-3;

the method comprising:

(i) providing an intermediate molecule of Formula:

or a pharmaceutically acceptable salt thereof, wherein R 4 is alkyl substituted by an amino group, alkylaryl substituted by an amino group, or alkylarylalkyl substituted by an amino group;

and

(ii) coupling the amino group with a chelator comprising at least one —CO 2 H group, to provide a compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein R 4 is alkyl substituted by an amide-linked chelator moiety, alkylaryl substituted by an amide-linked chelator moiety, or alkylarylalkyl substituted by an amide-linked chelator moiety.

2. The method of claim 1 , wherein X is N.

3. The method of claim 1 , wherein X is O, S, or P.

4. The method of claim 1 , wherein:

X is N;

R 1 is hydrogen, alkyl, arylalkyl, alkylarylalkyl; and

R 2 and R 3 are each independently selected from the group consisting of hydrogen, alkyl, alkylaryl, aryl, arylalkyl, alkylarylalkyl, and heterocyclylalkyl.

5. The method of claim 1 , wherein R 2 or R 3 comprises the following structure,

wherein:

n is 0-6; and

R z is selected from the group consisting of alkyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, and heterocyclyl.

6. The method of claim 5 , wherein the compound of Formula (I) is of Formula:

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the compound of Formula (I) is of Formula:

or a pharmaceutically acceptable salt thereof, wherein R p is an α-amino protecting group.

8. The method of claim 1 , wherein the amide-linked chelator moiety is of Formula:

wherein one of D 1 and D 2 is a hydrogen and the other is:

wherein:

o, p, q, r, s, t, and u are each independently 1-6; and

v, w, x, and y are each independently 1-3.

9. The method of claim 8 , wherein o, r, s, t, and u are each 1, and p and q are each 2.

10. The method of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

11. The method of claim 1 , wherein R 4 of the intermediate molecule has the structure:

12. The method of claim 1 , wherein the intermediate molecule is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

13. The method of claim 1 , wherein the intermediate molecule is prepared by coupling a hydroxylamine of Formula:

with a carboxylic acid compound of Formula:

to provide the intermediate molecule, or pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the intermediate molecule is prepared by coupling hydroxylamine:

with a carboxylic ester prepared from a carboxylic acid of Formula:

to provide a hydroxamic acid compound of Formula:

and contacting the hydroxamic acid compound with a compound of Formula:

Y-R 4

wherein Y is a leaving group,

to provide the intermediate molecule, or pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein the hydroxamic acid compound is of Formula:

16. The method of claim 1 , wherein the chelator comprising at least one —CO 2 H group is selected from the group consisting of:

2-{bis[2-(bis{[(tert-butyl)oxycarbonyl]methyl}amino)ethyl]amino}acetic acid and

2-(1,4,7,10-tetraaza-4,7,10-tris{[tert-butyl)oxycarbonyl]methyl}-cyclododecyl)acetic acid.

17. The method of claim 1 , further comprising treating the compound of Formula (I) with an imaging agent to provide a diagnostic agent of Formula (I) comprising the imaging agent bound to the chelator moiety;

wherein the imaging agent is selected from the group consisting of a non-metallic isotope, an echogenic substance, an optical reporter, a boron neutron absorber, a paramagnetic metal ion, a ferromagnetic metal, a gamma-emitting radioisotope, a positron-emitting radioisotope, and an x-ray absorber.

18. The method of claim 17 , wherein the imaging agent is a Gd(III) paramagnetic metal ion.

19. The method of claim 17 , wherein the imaging agent is a gamma-emitting radioisotope or positron-emitting radioisotope selected from the group consisting of 111 In, 62 Cu, 64 Cu, 67 Ga, 68 Ga, and 153 Gd.

20. The method of claim 17 , wherein the diagnostic agent is selected from the group consisting of:

Assignments (11)