US 5,567,411 AGranted

Dendritic amplifier molecules having multiple terminal active groups stemming from a benzyl core group

AssigneeThe State of Oregon Acting by and through the State Board of Higher Education on Behalf of the University of Oregon

InventorsJohn F. W. Keana, Vladimir Martin, William H. Ralston

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Abstract

Dendritic derivatives of 3,5-bis(aminomethyl)benzene and aminomethyl benzene core groups are disclosed. In each derivative, termed an "amplifier" because the dendritic structure on each molecule terminates with multiple termini to each of which an "active group" can be attached, the desired effect of the active group per mole is amplified compared to conventional compounds having only one active group per molecule. Amplifier molecules can include a targeting group permitting the molecules to preferentially attach to a particular anatomical or physiological situs. Active groups are any of various pharmacologically or therapeutically active moieties, including moieties useful for magnetic-resonance contrast enhancement. The dendritic structures comprise linkers and branch groups covalently bonded to each other in any of various structural combinations. The amplifiers can be prepared as a solution or mixture with a physiologically compatible carrier for administration to a warm-blooded animal subject. Also disclosed are methods for using the compounds in diagnosis and therapy, such as obtaining a magnetic resonance image of a subject.

Claims30

Dependent claims

A compound having the structure:

##STR54## wherein:
(a) R1 is selected from a group consisting of:
R2,
R3, and
groups having the structure --(R4).sub.0-1 --(R5).sub.0-1 --(R6)(--R7).sub.0-1 wherein R4 is selected from a group consisting of C(O)--NH, C(S)--NH, C(O), O, NH--C(O), NH--C(S), NH--C(S)--NH, NH--C(O)--NH, C(O)--O, and O--C(O);
R5 is selected from a group consisting of aryls, aryl-(C.sub.1 -C.sub.20 alkyls), (C.sub.1 -C.sub.20 alkyl)-aryls, cycloalkyls, C.sub.1 -C.sub.20 alkyls and combinations thereof;
R6 is selected from a group consisting of H, C.sub.1 -C.sub.6 alkyls, C(O)--OH, C(O)--O--(C.sub.1 -C.sub.6 alkyls), C(O)--O.sup.- X.sup.+, NH.sub.2, NO.sub.2, NCS, NCO, OH, SH, B(OH).sub.2, and R4, wherein X is a monovalent metal cation;
and R7 is a targeting group;
and
(b) R2 and R3, which are the same or different, each has the structure ##STR55## wherein R8 and R9, which are the same or different, are a hydrogen or a group having the structure --R10--(R11)--(R12).sub.0-1 --(R13).sub.n and at least one of said R8 and R9 groups has the --R10--(R11)--(R12).sub.0-1 --(R13).sub.n structure, wherein
R10 is at least one structure selected from a group consisting of linkers and branch groups, the linkers and branch groups, when more than one is present in R10, being covalently bonded together in a series manner to form R10;
R11 is selected from a group consisting of --NH--C(O)--, --C(O)--NH--, --C(O)--, --NH--C(S)--, --C(S)--NH--, --NH--C(O)--NH--, --NH--C(S)--NH--, --NH--C(O)--O--, --O--C(O)--NH--, --C(O)--O--, and --O--C(O)--;
R12 is an aryl, C.sub.1 -C.sub.12 alkyl, (C.sub.1 -C.sub.12 alkyl)-aryl, cycloalkyl, aryl-(C.sub.1 -C.sub.12 alkyl), or a combination thereof;
and
R13 is an active group wherein n is 1 or 2.

12 more elements

A compound having the structure:

##STR57## wherein:
(a) R1 is selected from a group consisting of:
R2,
R3, and
groups having the structure --(R4).sub.0-1 --(R5).sub.0-1 --R6 (--R7).sub.0-1, wherein R4 is selected from a group consisting of C(O)--NH, C(S)--NH, C(O), O, NH--C(O), NH--C(S), NH--C(S)--NH, NH--C(O)--NH, C(O)--O, and O--C(O);
R5 is selected from a group consisting of aryls, aryl-(C.sub.1 -C.sub.20 alkyls), (C.sub.1 -C.sub.20 alkyl)-aryls, cycloalkyls, C.sub.1 -C.sub.20 alkyls, and combinations thereof;
R6 is selected from a group consisting of H, C.sub.1 -C.sub.6 alkyls, C(O)--OH, C(O)--O--(C.sub.1 -C.sub.6 alkyls), C(O)--O.sup.- X.sup.+, NH.sub.2, NO.sub.2, NCS, NCO, OH, SH, B(OH).sub.2, and R4, wherein X is a monovalent metal cation;
and R7 is a targeting group;
and
(b) R2 and R3, which are the same or different, each has the structure ##STR58## wherein R8 and R9, which are the same or different, are a hydrogen or a group having the structure --R10--R11)--(R12).sub.0-1 --(R13).sub.n and at least one of said R8 and R9 groups has the --R10--(R11)--(R12).sub.0-1 --(R13).sub.n structure, wherein
R10 is at least one structure selected from a group consisting of linkers and branch groups, the linkers and branch groups, when more than one is present in R10, being covalently bonded together in a series manner to form R10;
R11 is selected from a group consisting of --NH--C(O)--, --C(O)--NH--, --C(O)--, --NH--C(S)--, --C(S)--NH--, --NH--C(O)--NH--, --NH--C(S)--NH--, --NH--C(O)--O--, --O--C(O)--NH--, --C(O)--O--, and --O--C(O)--;
R12 is an aryl, C.sub.1 -C.sub.12 alkyl, (C.sub.1 -C.sub.12 alkyl)-aryl, cycloalkyl, aryl-(C.sub.1 -C.sub.12 alkyl), or a combination thereof;
and
R13 is an active group wherein n is 1 or 2.

12 more elements

A compound having the structure:

##STR60## wherein:
(a) R1 is selected from a group consisting of:
R2,
R3, and
groups having the structure --(R4).sub.0-1 --(R5).sub.0-1 --R6(--R7).sub.0-1 wherein R4 is selected from a group consisting of C(O)--NH, C(S)--NH, C(O), O, NH--C(O), NH--C(S), NH--C(S)--NH, NH--C(O)--NH, C(O)--O, and O--C(O);
R5 is selected from a group consisting of aryls, aryl-(C.sub.1 -C.sub.20 alkyls), (C.sub.1 -C.sub.20 alkyl)-aryls, cycloalkyls, C.sub.1 -C.sub.20 alkyls, and combinations thereof;
R6 is selected from a group consisting of H, C.sub.1 -C.sub.6 alkyls, C(O)--OH, C(O)--O--(C.sub.1 -C.sub.6 alkyls), C(O)--O.sup.- X.sup.+, NH.sub.2, NO.sub.2, NCS, NCO, OH, SH, B(OH).sub.2, and R4, wherein X is a monovalent metal cation;
and R7 is selected from a group consisting of polypeptides, proteins, antibodies, nucleic acids, carbohydrates, fatty acids, surfactants, glycerides, porphyrins, steroids, and enzyme inhibitors;
and
(b) R2 and R3, which are the same or different, each has the structure ##STR61## wherein R8 and R9, which are the same or different, are a hydrogen or a group having the structure --R10--(R11)--(R12).sub.0-1 --(R13).sub.n and at least one of said R8 and R9 groups has the --R10--(R11)--(R12).sub.0-1 --(R13).sub.n structure, wherein
R10 is at least one structure selected from a group consisting of linkers and branch groups, the linkers having the structure --(R14).sub.0-1 --R15-- or --R15--(R14).sub.0-1 --, wherein R14 is an aryl, a C.sub.1 -C.sub.12 alkyl, an aryl-(C.sub.1 -C.sub.12 alkyl), a cycloalkyl, or a (C.sub.1 -C.sub.12 alkyl)-aryl or a combination thereof covalently bonded together in a series manner;
and R15 is selected from a group consisting of C(O)--NH, C(S)--NH, C(O), NH--C(O), NH--C(S), NH--C(S)--NH, NH--C(O)--NH, NH--C(O)--O, O--C(O)--NH, C(O)--O, and O--C(O);
and the branch groups having a structure selected from a group consisting of ##STR62## wherein R16 is a C.sub.1 -C.sub.6 alkyl;
the linkers and branch groups, when more than one of either or both is present in R10, being covalently bonded together in a series manner to form R10;
R11 is selected from a group consisting of --NH-C(O)--, --C(O)--NH--, --C(O)--, --NH--C(S)--, --C(S)--NH--, --NH--C(O)--NH--, --NH--C(S)--NH--, --NH--C(O)--O--, --O--C(O)--NH--, --C(O)--O--, and --O--C(O)--;
R12 is an aryl, C.sub.1 -C.sub.12 alkyl, (C.sub.1 -C.sub.12 alkyl)-aryl, cycloalkyl, aryl-(C.sub.1 -C.sub.12 alkyl), or a combination thereof;
and
R13 is selected from a group consisting of paramagnetic metal-ion chelators and nitroxides, and n is 1 or 2.

15 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/316,787Filed 29 Sep 1994 · continuation in part
Priority: 10 Nov 1986
Granted: 22 Oct 1996
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

A61K 49/20
Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations: containing free radicals , e.g.…
A61K 49/1812
Suspensions, emulsions, colloids, dispersions: liposomes, polymersomes, e.g. immunoliposomes
C07C 291/04
Containing nitrogen-oxide bonds: containing amino-oxide bonds
Y10S 436/803
Chemistry: analytical and immunological testing: stabe free radicals, e.g. spin immunoassay

Family

Serial928,943Parent of this continuation-in-part · filed 10 Nov 1986
Serial403,595Parent of this division · filed 5 Sep 1989
Serial887,542Parent of this division · filed 22 May 1992
Serial133,652Parent of this continuation-in-part · filed 6 Oct 1993
US 5,412,148 AParent of this continuation-in-part
US 5,252,317 AParent of this division
US 5,135,737 AParent of this division
US 4,863,717 AParent of this continuation-in-part
US 5,567,411 AThis patent

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