Nitroxyl compound and diagnostic media based thereon useful for enhancing NMR imaging

Claim 2

A pharmaceutical diagnostic medium comprising an effective amount for NMR diagnosis of a compound of the formula ##STR10## wherein B is a pharmacologically acceptable protein, sugar, or lipid residue, or ##STR11## is a single or double bond, X is --(CH 2 ) n -- or, when is a single bond, also --NHCO(CH 2 ) n -- wherein n is an integer 0 to 4, m is 0, 1, or 2, R 1 is C 2-8 -alkyl substituted by hydroxy, C 2-6 -alkanoyloxy or C 1-6 -alkylidenedioxy, R 2 independently is one of the R 1 groups, hydrogen or C 1-4 -alkyl, R 3 and R 4 independently are C 1-4 -alkyl, and R 5 and R 6 independently are C 1-4 -alkyl or C 1-4 -alkyl substituted by hydroxy, and a pharmacologically acceptable carrier.

Claim 3

A diagnostic medium of claim 1, wherein B is a protein residue.

Claim 4

A diagnostic medium of claim 1, wherein m is 0 or 1.

Claim 5

A diagnostic medium of claim 1, wherein when X is --(CH 2 ) n --, n is 0 or 1.

Claim 6

A diagnostic medium of claim 1, wherein when X is --NHCO(CH 2 ) n --, n is 2, 3, or 4.

Claim 7

A diagnostic medium of claim 1, wherein said compound is the conjugate of beef serum albumin and 2,2,5,5-tetramethyl pyrrolidine-1-oxyl-3-carboxylic acid.

Claim 8

A compound of the formula ##STR12## wherein B is a pharmacologically acceptable protein, sugar, or lipid residue, or ##STR13## is a single or double bond, X is --(CH 2 )n-- or, when is a single bond, also --NHCO(CH 2 ) n -- wherein n is an integer 0 to 4, m is 0, 1, or 2, R 1 is C 2-8 -alkyl substituted by polyhydroxy, C 2-6 -alkanoyloxy or C 2-6 -alkylidenedioxy, R 2 independently is one of the R 1 groups, hydrogen or C 1-4 -alkyl, R 3 and R 4 independently are C 1-4 -alkyl, and R 5 and R 6 independently are C 1-4 -alkyl or C 1-4 -alkyl substituted by hydroxy, with the provisos that when R 3 -R 6 are each methyl or ethyl, is a double bond, m is 0, X is --(CH 2 ) n --, n is 0 or 1, B is --NR 1 R 2 and R 2 is H or methyl, then R 1 is not, 2,3-dihydroxypropyl or 1,1-dimethyl-2-hydroxyethyl; and when R 5 and R 6 are each alkyl, is a double bond and m and n are 0, then B is not a sugar residue.

Claim 9

A compound of the formula ##STR12## wherein B is a pharmacologically acceptable protein, sugar, or lipid residue, or ##STR13## is a single or double bond, X is --(CH 2 )n-- or, when is a single bond, also --NHCO(CH 2 ) n -- wherein n is an integer 0 to 4, m is 0, 1, or 2, R 1 is C 2-8 -alkyl substituted by polyhydroxy, C 2-6 -alkanoyloxy or C 2-6 -alkylidenedioxy, R 2 independently is one of the R 1 groups, hydrogen or C 1-4 -alkyl, R 3 and R 4 independently are C 1-4 -alkyl, and R 5 and R 6 independently are C 1-4 -alkyl or C 1-4 -alkyl substituted by hydroxy, with the provisos that when R 3 -R 6 are each methyl or ethyl, is a double bond, m is 0, X is --(CH 2 ) n --, n is 0 or 1, B is --NR 1 R 2 and R 2 is H or methyl, then R 1 is not, 2,3-dihydroxypropyl or 1,1-dimethyl-2-hydroxyethyl; and when R 5 and R 6 are each alkyl, is a double bond and m and n are 0, then B is not a sugar residue.

Claim 10

The conjugate of beef serum albumin and 2,2,5,5-tetramethyl pyrrolidine-1-oxyl-3-carboxylic acid, a compound of claim 7.

Claim 11

A compound of claim 7, wherein B is a protein residue.

Claim 12

A compound of claim 7, wherein m is 0 or 1.

Claim 13

A compound of claim 7, wherein when X is --(CH 2 ) n --, n is 0 or 1.

Claim 14

A compound of claim 7, wherein when X is --NHCO(CH 2 ) n --, n is 2, 3 or 4.

Claim 15

A diagnostic medium comprising an effective amount for NMR diagnosis of a compound of claim 7 and a pharmacologically acceptable carrier.

Claim 16

A diagnostic medium of claim 13, wherein the compound is a clathrate in a liposome.

Claim 17

A compound of claim 7, wherein B is albumin or an antibody.

Claim 18

A compound of claim 7, wherein B is an immunoglobulin or a monoclonal antibody.

Claim 19

A diagnostic medium of claim 1, wherein m is 2.

Claim 20

A diagnostic medium of claim 1, wherein B is NR 1 R 2 and R 1 is C 2-6 -alkanoyloxy or C 1-6 -alkylidenedioxy.

Claim 21

A diagnostic medium of claim 1, wherein R 5 or R 6 is C 1-4 -alkyl substituted by hydroxy.

Claim 22

A diagnostic medium of claim 1, wherein B is NR 1 R 2 and R 5 or R 6 is C 1-4 -alkyl substituted by hydroxy.

Claim 23

A diagnostic medium of claim 20, wherein X is --(CH 2 ) n -- and n is 0.

Claim 24

A diagnostic medium of claim 1, wherein B is a sugar residue.

Claim 25

A diagnostic medium of claim 1, wherein B is a lipid residue.

Claim 26

A diagnostic medium of claim 1, wherein B is --NR 1 R 2 .

Claim 27

A diagnostic medium of claim 1, wherein said compound is 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid (2-hydroxyethyl)amide.

Claim 28

A diagnostic medium of claim 1, wherein said compound is 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid (2,3-dihydroxypropyl)amide.

Claim 29

2,2,5,5-Tetramethylpyrrolidine-1-oxyl-3-carboxylic acid [2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl]-amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid (1,3-dihydroxyprop-2-yl)amide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid [N-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-N-methyl]amide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid N-(2,3-dihydroxypropyl)-N-methylamide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid (2,3,4-trihydroxybutyl)amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid [N-(2,3,4,5,6-pentahydroxyhexyl)-N-methyl]-amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid (2,3-dihydroxypropyl)amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid bis(2-hydroxyethyl)amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid [N-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-N-methyl]amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid N-(2,3-dihydroxypropyl)-N-methylamide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid [2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl]amide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid (2,3,4-trihydroxybutyl)amide,

Claim 30

2,2,5,5-Tetramethylpyrrolidine-1-oxyl-3-carboxylic acid [2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl]-amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid (1,3-dihydroxyprop-2-yl)amide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-ylmethyl)amide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid [N-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-N-methyl]amide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid N-(2,3-dihydroxypropyl)-N-methylamide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid (2,3,4-trihydroxybutyl)amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid [N-(2,3,4,5,6-pentahydroxyhexyl)-N-methyl]-amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid (2,3-dihydroxypropyl)amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid bis(2-hydroxyethyl)amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid [N-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-N-methyl]amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid N-(2,3-dihydroxypropyl)-N-methylamide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid [2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl]amide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid (2,3,4-trihydroxybutyl)amide,

Claim 31

2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid (5-hydroxy-2,2-dimethyl-1,3-dioxepan-6-yl)amide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid (1,3,4-trihydroxybut-2-yl)amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid (5-hydroxy-2,2-dimethyl-1,3-dioxepan-6-yl)amide, 2,2,5,5-tetramethylpyrrolidine-1-oxyl-3-carboxylic acid (1,3,4-trihydroxybut-2-yl)amide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid [N-(2,3,4,5,6-pentahydroxyhexyl)-N-methyl]-amide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid (1,3-dihydroxyprop-2-yl)amide, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid (5-hydroxy-2,2-dimethyl-1,3-dioxepan-6-yl)amide, succinic acid N-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl]-N'-(2,2,6,6-tetramethyl-1-oxylpiperidin-4-yl) diamide, succinic acid [N-(2,2,6,6-tetramethyl-1-oxylpiperidin-4-yl)-N'-(2,3,4-trihydroxybutyl)] diamide, (1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)-acetic acid [N-(2,3,4,5,6-pentahydroxyhexyl)-N-methyl]amide, or succinic acid [N-(1-oxyl-2,2,5,5-tetramethylpyrrolidin-3-yl)-N'-(2,3,4,5,6-pentahydroxyhexyl)] diamide, each a compound of claim 7.

Claim 32

A compound of claim 7, wherein B is a sugar residue.

Claim 33

A compound of claim 7, wherein B is a lipid residue.

Claim 34

A compound of claim 7, wherein B is --NR 1 R 2 .

Claim 35

A diagnostic medium of claim 24, wherein R 1 is alkyl substituted by hydroxy.

Claim 36

A compound of claim 30, wherein R 1 is alkyl substituted by hydroxy.