Thioether conjugates
First Claim
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1. A compound of Formula (I):
- ##STR32## in which D is an anthracycline antibiotic;
n is an integer from 1 to 10;
p is an integer from 1 to 6;
Y is O or NH2+ Cl- ;
a is 0 or 1;
q is about 1 to about 10;
X is a ligand that specifically binds with a target cell population; and
A is a succinimido moiety;
wherein the anthracycline antibiotic is bound through the 13-keto position of the anthracycline.
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Abstract
Provided are drug/ligand compounds of Formula (I): ##STR1## in which D is a drug moiety;
n is an integer from 1 to 10;
p is an integer from 1 to 6;
Y is O or NH2+ C1- ;
z is 0 or 1;
q is about 1 to about 10;
X is a ligand; and,
A is a Michael Addition Adduct.
In a preferred embodiment, the ligand is an immunoglobulin, preferably a chimeric antibody or fragment thereof. Also provided are formulations comprising as an active ingredient a compound of Formula (I), intermediates useful for preparing the compounds of Formula (I), processes for preparing the compounds of Formula (I), and methods for using the compounds of the invention.
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Citations
52 Claims
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1. A compound of Formula (I):
- ##STR32## in which D is an anthracycline antibiotic;
n is an integer from 1 to 10;p is an integer from 1 to 6; Y is O or NH2+ Cl- ; a is 0 or 1; q is about 1 to about 10; X is a ligand that specifically binds with a target cell population; and A is a succinimido moiety; wherein the anthracycline antibiotic is bound through the 13-keto position of the anthracycline. - View Dependent Claims (7, 8, 9, 10, 11, 35)
- ##STR32## in which D is an anthracycline antibiotic;
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2. An anthracycline antibiotic conjugate compound of Formula (Ia):
- ##STR33## in which R1 is --CH3, --CH2 OH, --CH2 OCO(CH2)3 CH3 or --CH2 OCOCH(C2 H5)2 ;
R3 is --OCH3, --OH or hydrogen; R4 is --NH2, --NHCOCF3, 4-morpholinyl, 3-cyano-4-morpholinyl, 1-piperidinyl, 4-methoxy-1-piperidinyl, benzylamine, dibenzylamine, cyanomethyl amine or 1-cyano-2-methoxyethyl amine; R5 is --OH, --OTHP or hydrogen; R6 is --OH or hydrogen, provided that R6 is not --OH when R5 is --OH or --OTHP; n is an integer from 1 to 10; p is an integer from 1 to 6; Y is O or NH2+ Cl31 ; z is 0 or 1; q is about 1 to about 10; and X is a ligand that specifically binds with a target cell population. - View Dependent Claims (12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38)
- ##STR33## in which R1 is --CH3, --CH2 OH, --CH2 OCO(CH2)3 CH3 or --CH2 OCOCH(C2 H5)2 ;
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3. A compound of Formula (Ib):
- ##STR34## in which n is an integer from 1 to 10;
q is about 1 to about 10; and X is a ligand that specifically binds with a target cell population. - View Dependent Claims (39, 40, 41, 42, 43)
- ##STR34## in which n is an integer from 1 to 10;
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4. A compound of Formula (Ic):
- ##STR35## in which q is about 4 to about 8; and
X is a ligand that specifically binds with a target cell population. - View Dependent Claims (44, 45, 46, 47, 48, 49)
- ##STR35## in which q is about 4 to about 8; and
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5. A formulation which comprises as an active ingredient a compound of Formula (Ia):
- ##STR36## in which R1 is --CH3, --CH2 OH, --CH2 OCO(CH2)3 CH3 or --CH2 OCOCH(C2 H5)2 ;
R3 is --OCH3, --OH or hydrogen; R4 is --NH2, --NHCOCF3, 4-morpholinyl, 3-cyano-4-morpholinyl, 1-piperidinyl, 4-methoxy-1-piperidinyl, benzylamine, dibenzylamine, cyanomethyl amine or 1-cyano-2-methoxyethyl amine; R5 is --OH, --OTHP or hydrogen; R6 is --OH or hydrogen, provided that R6 is not --OH when R5 is --OH or --OTHP; n is an integer from 1 to 10; p is an integer from 1 to 6; Y is O or NH2+ Cl- ; z is 0 or 1; q is about 1 to about 10; and X is a ligand that specifically binds with a target cell population; in a pharmaceutically acceptable amount associated with a pharmaceutically acceptable carrier, diluent or excipient therefor.
- ##STR36## in which R1 is --CH3, --CH2 OH, --CH2 OCO(CH2)3 CH3 or --CH2 OCOCH(C2 H5)2 ;
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6. A formulation which comprises as an active ingredient a compound of Formula (Ib):
- ##STR37## in which n is an integer from 1 to 10;
q is about 1 to about 10; and X is a ligand reactive with a selected target cell population; in a pharmacutically acceptable amount associated with a pharmaceutically acceptable carrier, diluent or excipient therefor. - View Dependent Claims (51)
- ##STR37## in which n is an integer from 1 to 10;
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50. A compound of Formula (Id):
- ##STR38## in which q is from about 4 to about 8 and Ig is a relaxed chimeric BR96 antibody, or a fragment thereof.
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52. A formulation which comprises as an active ingredient a compound of Formula (Id):
- ##STR39## in which q is from about 4 to about 8 and Ig is a relaxed chimeric BR96 antibody, or a fragment thereof, associated with a pharmaceutically acceptable carrier, diluent or excipient therefor.
Specification