Bisamide bisthiol compounds useful for making technetium radiodiagnostic renal agents

Claim 2

Compounds having the structural formula: or wherein R and R 6 are each selected from hydrogen, substituted or unsubstituted lower alkyl or - COR 9 where R 9 is selected from hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted amino, glycine ester or an activated leaving group: R is selected from hydrogen, or substituted or unsubstituted lower alkyl; R 2 and R 3 are each selected from hydrogen or a thiol protecting group; and R 4 , R 5 , R 7 and R 8 are each selected from hydrogen or lower alkyl; and salts thereof.

Claim 3

A complex formed by reacting said compound of claim 1 with technetium in the presence of a reducing agent.

Claim 4

The complex of claim 2 where said reducing agent is a dithionite group, a stannous ion or a ferrous ion.

Claim 5

A compound of claim 1 wherein R 9 is selected from halide, phenoxy, pentachlorophenoxy, N-oxy-succinimide, and mercapto groups.

Claim 6

A compound of claim 1 wherein R 2 and R 3 are each independently a group selected from acetamidomethyl, lower alkylaminocarbonyl, lower alkanoylaminomethyl, aroylaminomethyl, t-butyl, arylmethyl, aroyl, aryloxycarbonyl, and lower alkoxycarbonyl.

Claim 7

A compound of claim 5 wherein R 2 and R 3 are groups selected from acetamidomethyl, benzoyl, diphenylmethyl, ethylaminocarbonyl, t-butyl, and trityl.

Claim 8

A compound of claim 6 wherein both R 2 and R 3 are acetamidomethyl.

Claim 9

A technetium complex having the structural formula: or wherein R and R 6 are each selected from hydrogen, substituted or unsubstituted lower alkyl or - COR 9 where R 9 is selected from hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted amino, glycine ester or an activated leaving group; R' is selected from hydrogen or a substituted or unsubstituted lower alkyl; and R 4 , R 5 , R 7 and R 8 are each selected from hydrogen or lower alkyl; and salts thereof.

Claim 10

A technetium complex having the structural formula: or wherein R and R 6 are each selected from hydrogen, substituted or unsubstituted lower alkyl or - COR 9 where R 9 is selected from hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted amino, glycine ester or an activated leaving group; R' is selected from hydrogen or a substituted or unsubstituted lower alkyl; and R 4 , R 5 , R 7 and R 8 are each selected from hydrogen or lower alkyl; and salts thereof.

Claim 11

A complex of claim 8 wherein R 9 is selected from halide, phenoxy, pentachlorophenoxy, N-oxy-succinimido, and mercapto groups.

Claim 12

A kit for preparing a radiopharmaceutical preparation comprising a sealed vial containing a predetermined quantity of a compound of claim 1 and a sufficient amount of reducing agent to label said compound with technetium.

Claim 13

The kit of claim 10 wherein R 9 is selected from halide, phenoxy, pentachlorphenoxy, N-oxy-succinimido, and mercapto groups.

Claim 14

The kit of claim 10 wherein R 2 and R 3 are each independently a group selected from lower acetamidomethyl, alkylaminocarbonyl, lower alkanoylaminomethyl, aroylaminomethyl, t-butyl, arylmethyl, aroyl, aryloxycarbonyl, and lower alkoxycarbonyl.

Claim 15

The kit of claim 12 wherein R 2 and R 3 are groups selected from acetamidomethyl, benzoyl, diphenylmethyl, ethylaminocarbonyl, t-butyl, and trityl.

Claim 16

The kit of claim 13 wherein both R 2 and R 3 are acetamidomethyl.

Claim 17

The kit of claim 10 wherein said reducing agent is a dithionite group, a stannous ion, or a ferrous ion.

Claim 18

A kit for preparing a radiopharmaceutical preparation comprising a sterilized, sealed vial comprising a lyophilized admixture of a reducing agent for technetium and a bisamido-bisthio compound capable of forming a 5 coordinate oxotechnetium complex in an aqueous solution having a pH in the range of about 5 to 8.

Claim 19

A kit for preparing a radiopharmaceutical preparation comprising a sterilized, sealed vial comprising a lyophilized admixture of a reducing agent for technetium and a bisamido-bisthio compound capable of forming a 5 coordinate oxotechnetium complex in an aqueous solution having a pH in the range of about 5 to 8.

Claim 20

The kit of claim 16 wherein said reducing agent is selected from stannous ion, a dithionite moiety, and ferrous ion.

Claim 21

The kit of claim 17 wherein said reducing agent is stannous chloride.

Claim 22

The kit of claim 16 wherein said bisamido-bisthio compound is selected from: N-(2-mercaptoethyl)-(2-mercaptoacetyl)glycinamide; N -[2-(benzoylthio)ethyl]-(2-benzoylthioacetyl)glycinamide; N-[2-(acetamidomethylthio)ethyl]-(2-acetamidomethylthio- acetyl)glycinamide; (2-mercaptoacetyl)glycyl-cysteine methyl ester; (2-benzoylthioacetyl)glycyl-(S-benzoyl)cysteine methyl ester; [2-(acetamidomethylthio)acetyl]glycyl-(S-acetamidomethyl)-cysteine methyl ester; (2-mercaptoacetyl)glycyl-cysteine; (2-benzoylthioacetyl)glycyl-(S-benzoyl)cysteine; [2-(acetamidomethylthio)acetyl]glycyl-(S-acetamidomethyl)-cysteine; (2-mercaptoacetyl)glycyl-cysteinyl-glycine methyl ester; (2-benzoylthioacethyl)glycyl-(S-benzoyl)cysteinyl-glycine methyl ester; [2-(acetamidomethylthio)acetyl]glycyl-(S-acetamidomethyl)-cysteinyl-glycine methyl ester; N-(2-mercaptoethyl)-N I- (1-carbomethoxy-2-mercaptoethyl)-oxamide; N-[2-(benzoylthio)ethyl]-N'-[1-carbomethoxy-2-(benzoylthio)-ethyl]oxamide; N-[2-(acetamidomethylthio)ethyl]-N'-[l-carbomethoxy-2-(acet- amidomethylthio)ethyl]oxamide; N,N'-bis(2-mercaptoethyl)oxamide; N,N'-bis[2-(benzoylthio)ethyl]oxamide; N,N'-bis[2-(acetamidomethylthio)ethyl]oxamide; (R,R)N,N'-bis(1-carbomethoxy-2-mercaptoethyl)oxamide; (R,R)N,N'-bis[1-carbomethoxy-2-(benzoylthio)ethyl]oxamide; and (R,R)N,N'-bis[1-carbomethoxy-2-(acetamidomethylthio)ethyl]-oxamide.

Claim 23

The kit of claim 16 wherein said bisamido-bisthio compound has a hydrophilic thiol protecting group.

Claim 24

The kit of claim 16 wherein said bisamido-bisthio compound has an acetamidomethyl thiol protecting group.

Claim 25

The kit of claim 16 wherein said bisamido-bisthio compound has two acetamidomethyl thiol protecting groups.

Claim 26

The kit of claim 16 wherein the sulfur atom at each end of said compound has a hydrophilic thiol protecting group.

Claim 27

The kit of claim 23 wherein said thiol group is acetamidomethyl.

Claim 28

A method for diagnosing kidney disfunction in a mammal comprising injecting into said mammal a technetium complex in accord with claim 8 in a suitable pharmacological carrier; and scanning the renal system of said mammal using radio- scintigraphic imaging apparatus.

Claim 29

Compounds having the structural formula: or wherein R and R 6 are each selected from hydrogen, substituted or unsubstituted lower alkyl or -COR 9 where R 9 is selected from hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted amino, glycine ester or an activated leaving group; R 1 is selected from hydrogen, or substituted or unsubstituted lower alkyl; R 2 and R 3 are each selected from hydrogen or a thiol protecting group; and R 4 , and R5are each selected from hydrogen or lower alkyl; and salts thereof.

Claim 30

Compounds having the structural formula: or wherein R and R 6 are each selected from hydrogen, substituted or unsubstituted lower alkyl or -COR 9 where R 9 is selected from hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted amino, glycine ester or an activated leaving group; R 1 is selected from hydrogen, or substituted or unsubstituted lower alkyl; R 2 and R 3 are each selected from hydrogen or a thiol protecting group; and R 4 , and R5are each selected from hydrogen or lower alkyl; and salts thereof.

Claim 31

A complex formed by reacting said compound of claim 26 with technetium in the presence of a reducing agent.

Claim 32

A compound in accord with claim 26 wherein R 2 and R 3 are groups selected from acetamidomethyl, benzoyl, diphenylmethyl, ethylaminocarbonyl, t-butyl, and trityl.

Claim 33

The compound of claim 28 wherein R 2 and R 3 are ace t-amidomethyl.

Claim 34

A kit for preparing a radiopharmaceutical preparation comprising a sealed vial containing predetermined quantity of a compound of claim 26 and a sufficient amount of reducing agent to label said compound with technetium.

Claim 35

The kit of claim 30 wherein said reducing agent is a stannous ion.

Claim 36

The kit of claim 30 wherein said compound has acetamidomethyl thiol protecting groups.

Claim 37

The kit of claim 30 wherein said compound and said reducing agent are lyophilized in a sterile vial and said compound is capable of forming a 5 coordinate oxotechnetium complex in an aqueous solution having a pH in the range of about 5 to 8.

Claim 38

(2-Benzoylthioacetyl)-glycyl-(S-benzoyl)cysteine methyl ester.

Claim 39

(2-Benzoylthioacetyl)-glycyl-(S-benzoyl)cysteine methyl ester.

Claim 40

A kit for preparing a radiopharmaceutical preparation comprising a sealed vial containing predetermined quantity of a compound of claim 34 and a sufficient amount of reducing agent to label said compound with technetium.

Claim 41

(2-Acetamidomethylthio)acetyl-glycyl-(S-acetamidomethyl)cysteine methyl ester.

Claim 42

(2-Acetamidomethylthio)acetyl-glycyl-(S-acetamidomethyl)cysteine methyl ester.

Claim 43

A kit for preparing a radiopharmaceutical preparation comprising a sealed vial containing predetermined quantitiy of a compound of claim 36 and a sufficient amount of reducing agent to label said compound with technetium.

Claim 44

(2-Acetamidomethylthio)acetyl-glycyl-(S-acetamidomethyl)cysteine.

Claim 45

(2-Acetamidomethylthio)acetyl-glycyl-(S-acetamidomethyl)cysteine.

Claim 46

A kit for preparing a radiopharmaceutical preparation comprising a sealed vial containing predetermined quantity of a compound of claim 38 and a sufficient amound of reducing agent to label said compound with technetium.

Claim 47

(2-Benzoylthioacetyl)glycyl-(S-benzoyl)cysteinyl-glycine methyl ester.

Claim 48

(2-Benzoylthioacetyl)glycyl-(S-benzoyl)cysteinyl-glycine methyl ester.

Claim 49

A kit for preparing a radiopharmaceutical preparation comprising a sealed vial containing predetermined quantity of a compound of claim 40 and a sufficient amount of reducing agent to label said compound with technetium.

Claim 50

N-[(2-benzoylthio)ethyl]-N-'[1-carbomethoxy-(2-benzoylthio)ethyl]-oxamide.

Claim 51

N-[(2-benzoylthio)ethyl]-N-'[1-carbomethoxy-(2-benzoylthio)ethyl]-oxamide.

Claim 52

A kit for preparing a radiopharmaceutical preparation comprising a sealed vial containing predetermined quantity of a compound of claim 42 and a sufficient amount of reducing agent to label said compound with technetium.

Claim 53

N,N'-bis(1-carbomethoxy-2-benzoylthioethyl)oxamide.

Claim 54

N,N'-bis(1-carbomethoxy-2-benzoylthioethyl)oxamide.

Claim 55

A kit for preparing a radiopharmaceutical preparation comprising a sealed vial containing predetermined quantity of a compound of claim44 and a sufficient amount of reducing agent to label said compound with technetium.