US 5,656,254 AGranted

Polyaza heteroatom-bearing ligands and metal complexes thereof for imaging or radiotherapy

AssigneeBracco International B.V.

InventorsKondareddiar Ramalingam, Natarajan Raju

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Abstract

Novel compounds containing a heteroatom-bearing bridge and novel complexes of these compounds with metals. The novel compounds and complexes are useful in diagnostic and therapeutic methods.

Claims16

Dependent claims

A diagnostic method comprising administering to a subject in need thereof a complex, and imaging said subject, the complex comprising a metal and a compound, the compound having the following formula Ia, Ib or Ic;

##STR63## where O is the group -(C(RR)).sub.m1 -Y.sup.1 -(C(RR)).sub.m2 -(Y.sup.2 -(C(RR).sub.m3).sub.n -, where Y.sup.1 and Y.sup.2 are independently --NR--, --O--, --S--, --SO--, --SO.sub.2 --, or --Se--;
n is an integer selected from 0 or 1;
and m1, m2 and m3 are integers independently selected from 0 to 4, provided that the sum of m1 and m2 is greater than zero;
with the proviso that if the R of --NR-- of Y.sup.1 is not hydrogen, and n=0, then either m1=0 or m2=0;
all R and R* groups are independently:
(i) R.sup.2 ;
(ii) halogen;
(iii) --OR.sup.2 ;
(iv) --C(O)--OR.sup.2 ;
(v) --C(O)--N(R.sup.2).sub.2 ;
(vi) --N(R.sup.2).sub.2 ;
(vii) -alkyl--C(O)--OR.sup.2 ;
(viii) -alkyl--C(O)--N(R.sup.2).sub.2 ;
(ix) -alkyl--N(R.sup.2).sub.2 ;
(x) -aryl-C(O)--OR.sup.2 ;
(xi) -aryl-C(O)-N(R.sup.2).sub.2 ;
(xii) -aryl-N(R.sup.2).sub.2 ;
(xiii) acyl;
(xiv) acyloxy;
(xv) heterocyclo;
(xvi) hydroxyalkyl;
(xvii) --SO.sub.2 --R.sup.2 ;
(xviii) -alkyl--SO.sub.2 --R.sup.2 ;
(xix) -(A)p-R.sup.3, where A is a linking group, p is 0 or a positive integer, and R.sup.3 is a bioactive moiety;
or
(xx) two R groups, or an R group and an R* group, taken together with the one or more atoms to which they are bonded, form a saturated or unsaturated, spiro or fused, carbocyclic or heterocyclic ring which may be unsubstituted or substituted by one or more groups selected from the groups (i) to (xix) above;
with the proviso that a carbon atom bearing an R group is not directly bonded to more than one heteroatom;
R.sup.1 is hydrogen, a thiol protecting group, or the group --(A)p--R.sup.3 defined above;
and
R.sup.2 is independently hydrogen, alkyl, alkenyl, alkynyl, or aryl.

27 more elements

A kit comprising a compound and a pharmaceutically acceptable reducing agent, the compound having the following formula Ia, Ib or Ic:

##STR65## where O is the group -(C(RR)).sub.m1 -Y.sup.1 (C(RR)).sub.m2 -(Y.sup.2 -(C(RR)).sub.m3).sub.n, where Y.sup.1 and Y.sup.2 are independently --NR--, --O--, --S--, --SO--, --SO.sub.2 -, or --Se--;
n is an integer selected from 0 or 1;
and m1, m2 and m3 are integers independently selected from 0 to 4, provided that the sum of m1 and m2 is greater than zero;
with the proviso that if the R of --NR-- of Y.sup.1 is not hydrogen, and n=0, then either m1=0 or m2=0;
all R and R* groups are independently:
(i) R.sup.2 ;
(ii) halogen;
(iii) --OR.sup.2 ;
(iv) --C(O)--OR.sup.2 ;
(v) --C(O)--N(R.sup.2);
(vi) --N(R.sup.2).sub.2 ;
(vii) alkyl-C(O)--OR.sup.2 ;
(viii) alkyl-C(O)--N(R.sup.2).sub.2 ;
(ix) -alkyl-N(R.sup.2).sub.2 ;
(x) -aryl-C(O)--OR.sup.2 ;
(xi) -aryl-C(O)--N(R.sup.2);
(xii) -aryl-N(R.sup.2).sub.2 ;
(xiii) acyl;
(xiv) acyloxy;
(xv) heterocyclo;
(xvi) hydroxyalkyl;
(xvii) --SO.sub.2 --R.sup.2 ;
(xviii) -alkyl-SO.sub.2 --R.sup.2 ;
(xix) -(A)p-R.sup.3, where A is a linking group, p is 0 or a positive integer, and R.sup.3 is a bioactive moiety;
or
(xx) two R groups, or an R group and an R* group, taken together with the one or more atoms to which they are bonded, form a saturated or unsaturated, spiro or fused, carbocyclic or heterocyclic ring which may be unsubstituted or substituted by one or more groups selected from the groups (i) to (xix) above;
with the proviso that a carbon atom bearing an R group is not directly bonded to more than one heteroatom;
R.sup.1 is hydrogen, a thiol protecting group, or the group -(A)p-R.sup.3 defined above;
and
R.sup.2 is independently hydrogen, alkyl, alkenyl, alkynyl;
or aryl.

28 more elements

A diagnostic method comprising administering to a subject in need thereof a complex, and imaging said subject;

the complex comprising a compound complexed with a metal, the compound having the following formula, Ia, Ib or Ic:
##STR66## where O is the group -(C(RR)).sub.m1 -Y.sup.1 -(C(RR)).sub.m2 -(Y.sup.2 -(C(RR)).sub.m3).sub.n, where Y.sup.1 and Y.sup.2 are independently --NR--, --O--, --S--, --SO--, --SO.sub.2, or --Se--;
n is an integer selected from 0 or 1;
and ml, m2 and m3 are integers independently selected from 0 to 4, provided that the sum of ml and m2 is greater than zero;
with the proviso that if the R of --NR-- of Y.sup.1 is not hydrogen, and n=0, then either m1=0 or m2=0;
with the further proviso that if the compound is of the formula Ic, Y.sup.1 is --SO.sub.2 --, and n=0, then either m1=0 or m2=0;
all R and R* groups are independently:
(i) R.sup.2 ;
(ii) halogen;
(iii) --OR.sup.2 ;
(iv) --C(O)--OR.sup.2 ;
(v) --C(O)--N(R.sup.2).sub.2 ;
(vi) --N(R.sup.2).sub.2 ;
(vii) -alkyl-C(O)--OR.sup.2 ;
(viii) -alkyl-C(O)--N(R.sup.2).sub.2 ;
(ix) -alkyl--N(R.sup.2).sub.2 ;
(x) -aryl-C(O)--OR.sup.2 ;
(xi) -aryl-C(O)--N(R.sup.2).sub.2 ;
(xii) -aryl-N(R.sup.2).sub.2 ;
(xiii) acyl;
(xiv) acyloxy;
(xv) heterocyclo;
(xvi) hydroxyalkyl;
(xvii) --SO.sub.2 --R.sup.2 ;
(xviii) -alkyl-SO.sub.2 --R.sup.2 ;
(xix) -(A)p-R.sup.3, where A is a linking group, p is 0 or a positive integer, and R.sup.3 is a bioactive moiety;
or
(xx) two R groups, or an R group and an R* group, taken together with the one or more atoms to which they are bonded, form a saturated or unsaturated, spiro or fused, carboeyclic or heterocyclic ring which may be unsubstituted or substituted by one or more groups selected from the groups (i) to (xix) above;
with the proviso that a carbon atom bearing an R group is not directly bonded to more than one heteroatom;
R.sup.1 is hydrogen, a thiol protecting group, or the group -(A)p-R.sup.3 defined above;
and R.sup.2 is independently hydrogen, alkyl, alkenyl, alkynyl, or aryl.

28 more elements

A method of radiotherapy of a discase comprising administering to a subject in need thereof a complex, the complex comprising a compound complexed with a radlioactive metal, the compound having the following formula, Ia, Ib or Ic:

##STR67## where Q is the group -(C(RR)).sub.m1 -Y.sup.1 -(C(RR)).sub.m2 -(Y.sup.2 -(C(RR)).sub.m3).sub.n -, where Y.sup.1 and Y.sup.2 are independently --NR--, --O--, --S--, --SO--, --SO.sub.2 -, or --Se--;
n is an integer selected from 0 or 1;
and m1, m2 and m3 are integers independently selected from 0 to 4, provided that the sum of m1 and m2 is greater than zero;
with the proviso that if the R of --NR-- of Y.sup.1 is not hydrogen, and n=0, then either m1=0 or m2=0;
with the further proviso that if the compound is of the formula Ic, Y.sup.1 is --SO.sub.2 --, and n=0, then either m1=0 or m2=0;
all R and R* groups are independently;
(xxi) R.sup.2 ;
(xxii) halogen;
(xxiii) --OR.sup.2 ;
(xxiv) --C(O)--OR.sup.2 ;
(xxv) --C(O)--N(R.sup.2).sub.2 :
(xxvi) --N(R.sup.2).sub.2 ;
(xxvii) -alkyl--C(O)--OR.sup.2 ;
(xxviii) -alkyl--C(O)--N(R.sup.2).sub.2 ;
(xxix) -alkyl--N(R.sup.2).sub.2 ;
(xxx) -aryl--C(O)--OR.sup.2 ;
(xxxi) -aryl--C(O)--N(R.sup.2).sub.2 ;
(xxxii) -aryl--N(R.sup.2).sub.2 ;
(xxxiii) acyl;
(xxxiv) acyloxy;
(xxxv) heterocyclo;
(xxxvi) hydroxyalkyl;
(xxxvii) --SO.sub.2 --R.sup.2 ;
(xxxviii) -alkyl--SO.sub.2 --R.sup.2 ;
(xxxix) -(A)p--R.sup.3, where A is a linking group, p is 0 or a positive integer, and R.sup.3 is a bioactive moiety;
or
(xl) two R groups, or an R group and an R* group, taken together with the one or more atoms to which they are bonded, form a saturated or unsaturated, spiro or fused, carbocyclic or heterocyclic ring which may be unsubstituted or substituted by one or more groups selected from the groups (i) to (xix) above;
with the proviso that a carbon atom bearing an R group is not directly bonded to more than one heteroatom;
R.sup.1 is hydrogen, a thiol protecting group, or the group -(A)p-R.sup.3 defined above;
and
R.sup.2 is independentIy hydrogen, alkyl, alkenyl, alkynyl, or aryl.

28 more elements

A kit comprising a compound and a pharmaceutically acceptable reducing agent, the compound having the following formula Ia, Ib or Ic:

##STR68## where O is the group -(C(RR)).sub.m1 -Y.sup.1 -(C(RR)).sub.m2 -(Y.sup.2 -(C(RR)).sub.m3).sub.n -, where Y.sup.1 and Y.sup.2 are independently --NR--, --O--, --S--, --SO--, --SO.sub.2 --, or --Se--;
n is an integer selected from 0 or 1;
and m1, m2 and m3 are integers independently selected from 0 to 4, provided that the sum of ml and m2 is greater than zero;
with the proviso that if the R of --NR-- of Y.sup.1 is not hydrogen, and n=0, then either m1=0 or m2=0;
with the further proviso that if the compound is of the formula Ic, Y.sup.1 is --SO.sub.2 -, and n=0, then either m0=0 or m2=0;
all R and R* groups are independently:
(i) R.sup.2 ;
(ii) halogen;
(iii) --OR.sup.2 ;
(iv) --C(O)--OR.sup.2 ;
(v) --C(O)--N(R.sup.2).sub.2 ;
(vi) --N(R.sup.2).sub.2 ;
(vii) -alkyl--C(O)--OR.sup.2 ;
(viii) -alkyl--C(O)--N(R.sup.2);
(ix) -alkyl--N(R.sup.2).sub.2 ;
(x) -alkyl-C(O)--OR.sup.2 ;
(xi) -aryl-C(O)--N(R.sup.2).sub.2 ;
(xii) -aryl-N(R.sup.2).sub.2 ;
(xiii) acyl
(xiv) acyloxy;
(xv) heterocyclo;
(xvi) hydroxyalkyl;
(xvii) --SO.sub.2 --R.sup.2 ;
(xviii) -alkyl--SO.sub.2 --R.sup.2 ;
(xix) -(A)p-R.sup.3, where A is a linking group, p is 0 or a positive integer, and R.sup.3 is a bioactive moiety;
or
(xx) two R groups, or an R group and an R* group, taken together with the one or more atoms to which they are bonded, form a saturated or unsaturated, spiro or fused, carbocyclic or heterocyclic ring which may be unsubstituted or substituted by one or more groups selected from the groups (i) to (xix) above;
with the proviso that a carbon atom bearing an R group is not directly bonded to more than one heteroatom;
R.sup.1 is hydrogen, a thiol protecting group, or the group -(A)p-R.sup.3 defined above;
and
R.sup.2 is independently hydrogen, alkyl, alkenyl, alkynyl, or aryl.

28 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/471,590Filed 6 Jun 1995 · division
Priority: 15 Jun 1993
Granted: 12 Aug 1997
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 307/71
Nitro radicals: attached in position 5
A61K 51/0478
Complexes or complex-forming compounds, i.e. wherein a radioactive metal is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group:…
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00

Family

Serial77,981Parent of this continuation-in-part · filed 15 Jun 1993
Serial242,093Parent of this division · filed 18 May 1994
US 5,656,254 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Novel compounds containing a heteroatom-bearing bridge and novel complexes of these compounds with metals. The novel compounds and complexes are useful in diagnostic and therapeutic methods.

Facts

Application

08/471,590Filed 6 Jun 1995 · division

Priority

15 Jun 1993

Granted

12 Aug 1997

Term ends

Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 307/71
Nitro radicals: attached in position 5
A61K 51/0478
Complexes or complex-forming compounds, i.e. wherein a radioactive metal is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group:…
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00