US 4,705,849 AGrant
Boronic Acid Adducts of Technetium-99m Dioxime Complexes
Issue Date:1987-11-10
•28 Claims
Abstract
Boronic acid adducts of technetium-99m dioxime complexes are useful for imaging the myocardium, hepatobiliary system, brain and blood pool in humans and other mammalian species.
Metadata
Assignee
- E. R. Squibb & Sons, Inc.
Inventors
- Adrian D. Nunn
- Thomas A. Feld
- Elizabeth N. Treher
Application Information
Application Number:US 7236018
Filing Date:1985-04-15
Priority Date:1985-04-15
Art Unit:223
Classifications
IPC:
A61K 4300A61K 4902C07F 1300
Field of Search:
4245344221.1;914,1061
Patent Drawings
This patent does not have any drawings.
Description
BRIEF DESCRIPTION OF THE INVENTION
Boronic acid adducts of technetium-99m dioxime complexes having the formula
are useful as imaging agents in humans and other mammalian species. In formula I, and throughout the specification, the symbols are as defined below.
X is an anion;
Y is a vicinal dioxime having the formula ##STR1## or a pharmaceutically acceptable salt thereof, and R.sub.1 and R.sub.2 are each independently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containing heterocycle, or together R.sub.1 and R.sub.2 are -(CR.sub.8 R.sub.9).sub.n - wherein n is 3, 4, 5 or 6 and R.sub.8 and R.sub.9 are each independently hydrogen or alkyl;
Z is a boron derivative having the formula
wherein R.sub.3 is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl (preferably having 2 to 19 carbons), carboxyalkenyl (preferably having 4 to 19 carbons), hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or and R.sub.4 R.sub.5 N)-alkyl and R.sub.4 and R.sub.5 are each independently hydrogen, alkyl, or arylalkyl, or R.sub.4 and R.sub.5 when taken together with the nitrogen atom to which they are attached form a 5 or 6-membered nitrogen containing heterocycle.
Listed below are definitions of the terms used to describe the complexes of this invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
The terms "alkyl" and "alkoxy" refer to both straight and branched chain groups. Those groups having 1 to 10 carbon atoms are preferred.
The term "alkenyl" refers to both straight and branched chain groups. Those groups having 2 to 10 carbon atoms are preferred.
The term "aryl" refers to phenyl and substituted phenyl. Preferred are phenyl and phenyl substituted with 1, 2 or 3 alkyl, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, alkoxyalkyl, halogen, amino, hydroxy, or formyl groups. Additional exemplary aryl groups for the instance wherein R.sub.3 is aryl include 3-(5-dimethylamino-1-naphthalenesulfonylamino)phenyl, 3-[4-[3'-phenyl-2'-pyrazolin-1,1'-yl]benzenesulfonyl-amino]phenyl, 3-(pyrenesulfamido)phenyl, 3-[4-(4-dimethylamino-1-naphthylazo)-3 -(methoxyphenyl-sulfamido)]phenyl, 3-[4-(4-dimethylamino-1-phenylazo)phenylthioureido]phenyl.
Preferred "cycloalkyl" and "cycloalkenyl" groups are those having 5,6 or 7 carbon atoms. The terms include those groups substituted with alkyl, alkoxy, aryl, carboxyalkyl, arylalkyl or (R.sub.4 R.sub.5 N)-alkyl groups.
The terms "halide", "halo" and "halogen" refer to fluorine, chlorine, bromine and iodine.
The expression "5 or 6-membered nitrogen containing heterocycle" refers to all 5 and 6-membered rings containing at least one nitrogen atom. Exemplary aliphatic groups are dehydro derivatives of a compound having the formula ##STR2## wherein m is 0 or 1 and A is O, N--R.sub.6 or CH--R.sub.6 wherein R.sub.6 is hydrogen, alkyl, aryl or arylalkyl. Such groups include pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-alkylpiperazinyl, 4-alkylpiperidinyl, and 3-alkylpyrrolidinyl groups. Also included within the expression "5 or 6-membered nitrogen containing heterocycle" are aromatic groups. Exemplary aromatic groups are pyrrolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, and pyrimidinyl groups. The above groups can be linked via a hetero atom or a carbon atom.
The expression "5 or 6-membered nitrogen or oxygen containing heterocycle" refers to all 5 and 6-membered rings containing at least one nitrogen or oxygen atom. Exemplary groups are those described above under the definition of the expression "5 or 6-membered nitrogen containing heterocycle". Additional exemplary groups are 1,4-dioxanyl and furanyl.
DETAILED DESCRIPTION OF THE INVENTION
Preparation of the complexes of this invention can best be accomplished using technetium-99m in the form of the pertechnetate ion. The pertechnetate ion can be obtained from commercially available technetium-99m parent-daughter generators; such technetium is in the +7 oxidation state. The generation of the pertechnetate ion using this type of generator is well known in the art, and is described in more detail in U.S. Pat. Nos. 3,369,121 and 3,920,995. These generators are usually eluted with saline solution and the pertechnetate ion is obtained as the sodium salt.
To prepare the complexes of this invention, pertechnetate ion (in the form of a salt) is combined with a source of anion, a boronic acid derivative having the formula ##STR3## or a pharmaceutically acceptable salt thereof, wherein R.sub.7 is hydrogen, alkyl or aryl, and a dioxime having the formula ##STR4## or a pharmaceutically acceptable salt thereof.
It is possible, in some instances, to prepare a boronic acid derivative of formula IV in situ. For example, when preparing a complex having an alkoxy group attached to the boron atom, it is possible to utilize boric acid and the appropriate alkanol as reactants.
The source of the anion moiety (X) can be water or it can be an acid or salt which dissociates to release an appropriate anion. Exemplary anionic moieties are hydroxyl, halide, isothiocyanato (N.dbd.C.dbd.S.sup..THETA.) and thiocyanato (S--C.dbd.N.sup..THETA.). The preferred anionic moieties are the halides, and chloride is the most preferred halide. If the source of the anion is not water, the source should be present in an appropriate concentration to compete effectively with any water that may be present during the reaction. It has been found that the source of anion should be present in the reaction mixture in a concentration of about 0.3 to 4.5 molar.
The boronic acid derivative of formula IV should preferably be present in a concentration of about 5 to 200 millimolar. The dioxime of formula II should preferably be present in a concentration. of about 9 to 43 millimolar.
The formation of the complex proceeds best if the mixture of pertechnetate ion, source of anion, boronic acid derivative, and dioxime is heated at about 25.degree. C. to 150.degree. C. for about 5 minutes to about 60 minutes, preferably at about 100.degree. C. to about 140.degree. C. for about 5 minutes to about 15 minutes. The reaction is preferably run in an aqueous medium at a pH of less than, or equal to, about 5.
The reaction mixture should also contain a reducing agent. Stannous ion is the preferred reducing agent, and can be introduced in the form of a stannous salt such as a stannous halide (e.g., stannous chloride or stannous fluoride). The reducing agent should be present in a concentration of about 1.5 micromolar to 6.6 millimolar.
Various complexing agents (also known in the art as chelating agents) can be included as part of the complexing reaction. The complexing agent should, of course, be pharmaceutically acceptable. Exemplary complexing agents are diethylenetriamine-pentaacetic acid (DTPA), ethylene glycol-bis(.beta.-aminoethyl ether)-N,N'-tetraacetic acid (EGTA), ethylenediamine tetraacetic acid (EDTA), citric acid, tartaric acid, malonic acid, etc.
The complexing reaction mixture can also include an accelerator (catalyst) which serves to improve the radiochemical purity (i.e., per cent of the radioactivity that is in the desired chemical form) of the product. Exemplary accelerators are the .alpha.-hydroxycarboxylic acids such as citric acid, tartaric acid, and malonic acid. A combination of DTPA and citric acid has been found to be preferred.
Working with the technetium-99 isotope, the structure of complexes of this invention has been investigated and is believed to be: ##STR5##
Because of the short half-life of technetium-99m (i.e., 6.02 hours), it is necessary to prepare the complexes of this invention at, or near, the site where they are to be used. A kit having all of the components, other than the pertechnetate ion, needed to prepare the boronic adducts of technetium-99m dioxime complexes of formula I is an integral part of this invention. Such a kit contains a source of anion, a boronic acid derivative of formula IV (or compounds which can react in situ to form such a derivative), or a pharmaceutically acceptable salt thereof, a dioxime of formula II, or a pharmaceutically acceptable salt thereof, and a reducing agent. It may optionally contain a complexing agent.
The kits of this invention can be formulated in aqueous solution. To optimize the stability of the kit, and to optimize the radiochemical purity of the labeled product, the pH of the kit should be adjusted to fall within the range of about 2.0 to 5.5 using a pharmaceutically acceptable acid or base (e.g., hydrochloric acid or sodium hydroxide). Preferably, the pH of the kit will be about 3.0. It is also preferred that the kit be in lyophilized form. While "wet" kits can be used, they are not as efficacious as the corresponding lyophilized kit.
The complexes of this invention are useful as imaging agents. More specifically, they are useful for imaging the myocardium and the hepatobiliary system in humans and other mammalian hosts. Those complexes of this invention which are neutral at physiological pH (i.e., pH 7.4) are also useful for imaging the brain in humans and other mammalian hosts. [The charge of the complexes of this invention is determined by the sum of the charges of the organic groups ("R.sub.1 ", "R.sub.2 " and "R.sub.3 ") attached to the boron atom and part of the dioximes.] Those complexes of this invention which contain the vicinal dioxime 1,2-ethanedione dioxime are also useful for imaging the blood pool of humans and other mammalian hosts.
The complexes of this invention can be administered to a host by bolus intravenous injection. The size of the host, and the imaging system used, will determine the quantity of radioactivity needed to produce diagnostic images. For a human host, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of technetium-99m.
The following examples are specific embodiments of this invention.
EXAMPLE 1
99mTc (chlorine)(dimethyl glyoxime).sub.3 methoxy boron and 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron
Into a 5 ml siliconized serum vial were measured 5.0 mg of dimethyl glyoxime, 0.5 ml of methanol, 2.0 mg of boric acid and 0.5 mg of stannous chloride in 5.mu.l of concentrated hydrochloric acid.
Sodium pertechnetate* in physiological saline (0.2 ml) was added to the vial which was then heated at 140.degree. C. for 30 minutes yielding 6%** of the 99mTc (chlorine)(dimethyl glyoxime).sub.3 methoxy boron as determined by HPLC (high pressure liquid chromatography). The reaction also yielded 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron. The complexes were separated by HPLC.
EXAMPLE 2
99mTc (chlorine)(dimethyl glyoxime).sub.3 ethoxy boron and 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron
Into a 5 ml siliconized vial were measured 2.0 mg of dimethyl glyoxime in 0.2 ml of ethanol, 2.0 mg of boric acid, 10 mg of citric acid in 0.1 ml of water, 100 mg of sodium chloride, 1.0 mg of diethylenetetramine pentaacetic acid, and approximately 50-60.mu.g of anhydrous stannous chloride in 1.mu.l of concentrated hydrochloric acid.
Sodium pertechnetate in physiological saline (0.5 ml) was added to the vial which was then heated at 100.degree. C. for 5 minutes yielding 4-5% of 99mTc (chlorine)(dimethyl glyoxime).sub.3 ethoxy boron. The reaction also yielded 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron. The complexes were separated by HPLC.
EXAMPLE 3
99mTc (chlorine)(dimethyl glyoxime).sub.3 propyloxy boron and 99mTc (chlorine)(dimethyl glyoxime).sub.3 -hydroxy boron
Following the procedure of example 1, but substituting n-propanol for methanol, yielded 99mTc (chlorine)(dimethyl glyoxime).sub.3 ethoxy boron. The reaction also yielded 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron. The complexes were separated by HPLC.
EXAMPLE 4
99mTc (chlorine)(dimethyl glyoxime).sub.3 butyloxy boron and 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron
Following the procedure of example 1, but substituting n-butanol for methanol, yielded 6% of 99mTc (chlorine)(dimethyl glyoxime).sub.3 ethoxy boron. The reaction also yielded 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron. The complexes were separated by HPLC.
EXAMPLE 5
99mTc (chlorine)(dimethyl glyoxime).sub.3 pentyloxy boron and 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron
Following the procedure of example 1, but substituting n-pentanol for methanol, yielded 99mTc (chlorine)(dimethyl glyoxime).sub.3 ethoxy boron. The reaction also yielded 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron. The complexes were separated by HPLC.
EXAMPLE 6
99mTc (chlorine)(dimethyl glyoxime).sub.3 hexyloxy boron
and 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron
Following the procedure of example 1, but substituting n-hexanol for methanol, yielded 8% of 99mTc (chlorine)(dimethyl glyoxime).sub.3 ethoxy boron. The reaction also yielded 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron. The complexes were separated by HPLC.
EXAMPLE 7
99mTc (chlorine)(dimethyl glyoxime).sub.3 octyloxy boron and 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron
Following the procedure of example 1, but substituting n-octanol for methanol, yielded 12% 99mTc (chlorine)(dimethyl glyoxime).sub.3 ethoxy boron. The reaction also yielded 99mTc (chlorine)(dimethyl glyoxime).sub.3 hydroxy boron. The complexes were separated by HPLC.
EXAMPLE 8
99mTc (chlorine)(dimethyl glyoxime).sub.3 1-methylpropyl boron
Following the procedure of example 2, but substituting 1-methylpropane boronic acid for boric acid, yielded the title complex.
EXAMPLE 9
99mTc (chlorine)(dimethyl glyoxime)3 methyl boron
Into a 5 ml siliconized serum vial were measured 2.0 mg of dimethyl glyoxime in 0.2 ml of ethanol, 2.0 mg of methane boronic acid, 10 mg of citric acid in 0.1 ml of water, 100 mg of sodium chloride, 1.0 mg of diethylenetetramine pentaacetic acid, and about 50-60.mu.g of stannous chloride in 1.mu.l of concentrated hydrochloric acid.
Sodium pertechnetate in physiological saline (0.5 ml) was added to the vial which was heated at 100.degree. C. for 5 minutes yielding 80-90% of the title complex.
EXAMPLE 10
99mTc (chlorine)(dimethyl glyoxime).sub.3 propyl boron
Following the procedure of example 9, but substituting 1-propane boronic acid for methane boronic acid, yielded the title complex.
EXAMPLE 11
99mTc (chlorine)(dimethyl glyoxime).sub.3 butyl boron
Following the procedure of example 9, but substituting 1-butane boronic acid for methane boronic acid, yielded the title complex.
EXAMPLE 12
99mTc (chlorine)(dimethyl glyoxime).sub.3 pentyl boron
Following the procedure of example 9, but substituting 1-pentane boronic acid for methane boronic acid, yielded 85% of the title complex.
EXAMPLE 13
99mTc (chlorine)(dimethyl glyoxime).sub.3 hexyl boron
Into a 5 ml siliconized serum vial were measured 3.0 mg of dimethyl glyoxime, 20 mg of 1-hexane boronic acid, sodium pertechnetate in physiological saline (0.2 ml) and 50.mu.l of saturated aqueous stannous tartrate. The vial was heated at 140.degree. C. for 5 minutes yielding 16% of the title complex.
EXAMPLE 14
99mTc (chlorine)(dimethyl glyoxime).sub.3 heptyl boron
Following the procedure of example 9, but substituting 8.0 mg of 1-heptane boronic acid for methane boronic acid and substituting 50.mu.l of saturated aqueous stannous tartrate for stannous chloride in hydrochloric acid, yielded 85% of the title complex.
EXAMPLE 15
99mTc (chlorine)(dimethyl glyoxime).sub.3 phenyl boron
Following the procedure of example 2, but substituting benzene boronic acid for boric acid, yielded 88% of the title complex.
EXAMPLE 16
99mTc (chlorine)(dimethyl glyoxime).sub.3 butyl boron
Into a 5 ml siliconized serum vial were measured 1.0 mg of dimethyl glyoxime in 0.1 ml of ethanol, 5.0 mg of 1-butane boronic acid in 50.mu.l of ethanol, 0.3 ml of saturated aqueous sodium chloride and 25.mu.l of saturated stannous pyrophosphate.
Sodium pertechnetate in physiological saline (0.1 ml) was added to the vial which was heated at 140.degree. C. for 5 minutes yielding 70% of the title complex.
EXAMPLE 17
99mTc (bromine)(dimethyl glyoxime).sub.3 butyl boron
Into a 5 ml siliconized serum vial were measured 1.0 mg of dimethyl glyoxime in 0.1 ml of ethanol, 5.0 mg of 1-butane boronic acid in 50.mu.l of ethanol, 0.3 ml of saturated aqueous potassium bromide, and 25.mu.l of saturated aqueous stannous pyrophosphate.
Sodium pertechnetate in physiological saline (0.1 ml) was added to the vial which was heated at 140.degree. C. for 5 minutes yielding 59% of the title complex.
EXAMPLE 18
99mTc (iodine)(dimethyl glyoxime).sub.3 butyl boron
Into a 5 ml siliconized serum vial were measured 1.0 mg of dimethyl glyoxime in 0.1 ml of ethanol, 5.0 mg of 1-butane boronic acid in 50.mu.l of ethanol, 0.3 ml of saturated aqueous potassium iodide, 25 .mu.l of saturated aqueous stannous pyrophosphate.
Sodium pertechnetate in physiological saline (0.1 ml) was added to the vial which was heated at 140.degree. C. for 5 minutes yielding 23% of the title complex.
EXAMPLE 19
99mTc (fluorine)(dimethyl glyoxime).sub.3 butyl boron
Into a 5 ml siliconized serum vial were measured 1.0 mg of dimethyl glyoxime in 0.1 ml of ethanol, 5.0 mg 1-butane boronic acid in 50.mu.l of ethanol, 0.3 ml of saturated aqueous sodium fluoride, and 25.mu.l of saturated aqeuous stannous pyrophosphate.
Sodium pertechnetate in physiological saline (0.2 ml) was added to the vial which was heated at 140.degree. C. for 5 minutes yielding 0.6% of the title complex.
EXAMPLE 20
99mTc (chlorine)(dimethyl glyoxime).sub.3 3-aminophenyl boron
Into a 5 ml siliconized serum vial were measured 5.0 mg of dimethyl glyoxime in methanol, 30 mg of 3-aminobenzene boronic acid, and 0.5 mg of stannous chloride in 5.mu.l of concentrated hydrochloric acid.
Sodium pertechnetate in physiological saline (0.2 ml) was added to the vial which was heated at 140.degree. C. for 5 minutes yielding 50% of the title complex.
EXAMPLE 21
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-methylphenyl boron
Following the procedure of example 2, but substituting p-toluene boronic acid for boric acid, yielded 88% of the title complex.
EXAMPLE 22
99mTc (chlorine)(dimethyl glyoxime).sub.3 3-(1-piperidinyl)propyl boron
Into a 5 ml siliconized serum vial were measured 0.5 mg of dimethyl glyoxime in 0.1 ml of ethanol 1.0 mg of 3-(1-piperidinyl)propane boronic acid monohydrochloride, 0.2 ml of saturated sodium chloride, 10 mg of citric acid, and 50.mu.l of saturated aqueous stannous pyrophosphate.
Sodium pertechnetate in physiological saline (0.2 ml) was added to the vial which was heated at 100.degree. C. for 5 minutes yielding 75% of the title complex.
EXAMPLE 23
99mTc (bromine)(dimethyl glyoxime).sub.3 3-(1-piperidinyl)propyl boron
Into a 5 ml siliconized serum vial were measured 1.0 mg of dimethyl glyoxime in 0.1 ml of ethanol, 5.0 mg of 3-(1-piperidinyl) propane boronic acid monohydrochloride, 0.4 ml of saturated potassium bromide, 10 mg of citric acid, and 50.mu.l of saturated aqueous stannous pyrophosphate.
Sodium pertechnetate in physiological saline (0.2 ml) was added to the vial which was heated at 100.degree. C. for 5 minutes yielding 13.8% of the title complex.
EXAMPLE 24
99mTc (chlorine)(dimethyl glyoxime).sub.3 3-(4-methyl-1-piperidinyl)propyl boron
Following the procedure of example 23, but substituting 0.2 ml of saturated sodium chloride for potassium bromide and 5.0 mg of 3-(4-methyl-1-piperidinyl) propane boronic acid monohydrochloride for 3-(1-piperidinyl)propane boronic acid monohydrochloride, yielded 94% of the title complex.
EXAMPLE 25
99mTc (chlorine)(dimethyl glyoxime).sub.3 3-(4-morpholinyl) propyl boron
Following the procedure of example 23, but substituting 0.2 ml of saturated sodium chloride for potassium bromide and 5.0 mg of 3-(4-morpholinyl)propane boronic acid monohydrochloride for 3-(1-piperidinyl) propane boronic acid monohydrochloride, yielded 87% of the title complex.
EXAMPLE 26
99mTc (chlorine)(dimethyl glyoxime).sub.3 3-(4-benzylpiperidinyl)propyl boron
Following the procedure of example 23, but substituting 0.2 ml of saturated sodium chloride for potassium bromide and 5.0 mg of 3-(4-benzyl-1-piperidinyl) propane boronic acid monohydrochloride for 3-(1-piperidinyl) propane boronic acid monohydrochloride, yielded the title complex.
EXAMPLE 27
99mTc (chlorine)(dimethyl glyoxime).sub.3 3-(5-dimethylamino-1-naphthalenesulfonylamino)phenyl boron
Following the procedure of example 23, but substituting 0.2 ml of saturated sodium chloride for potassium bromide and 5.0 mg of 3-(5-dimethylamino-1-naphthalenesulfonylamino) benzene boronic acid monohydrochloride for 3-(1-piperidinyl) propane boronic acid monohydrochloride, yielded the title complex.
EXAMPLE 28
99mTc (chlorine) (dimethyl glyoxime).sub.3 3-[methyl(2-phenylethyl)amino] propyl boron
Following the procedure of example 23, but substituting 0.2 ml of saturated sodium chloride for potassium bromide and 5.0 mg of 3-(methyl(2-phenylethyl)amino) propane boronic acid for 3-(1-piperidinyl) propane boronic acid for 3-(1-piperidinyl) propane boronic acid monohydorchloide, yielded the title complex.
EXAMPLE 29
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-hydroxy-1-butenyl boron
Following the procedure of example 2, but substituting 4-hydroxy-1-butene boronic acid for boric acid, yielded the title compound.
EXAMPLE 30
99mTc (chlorine)(dimethyl glyoxime).sub.3 (4-benzyl1-piperidinyl) boron
Following the procedure of example 22, but substituting 5 mg of (4-benzyl-1-piperidinyl) boronic acid monohydrochloride for 3-(1-piperidinyl) propane boronic acid monohydrochloride yielded 83% of the title complex.
EXAMPLE 31
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-(bromomethyl)phenyl boron and 99mTc (chlorine) (dimethyl glyoxime).sub.3 4-(ethoxymethyl)phenyl boron
Following the procedure of example 22, but substituting 1 mg of 4-(bromomethyl)benzene boronic acid for 3-(1-piperidinyl)propane boronic acid, monohydrochloride, yielded less than 5% of 99mTc (chlorine)(dimethyl glyoxime).sub.3 4-(bromomethyl)phenyl boron. The reaction also yielded 99mTc (chlorine) (dimethyl glyoxime).sub.3 4-(ethoxymethyl)phenyl boron. The complexes were separated by HPLC.
EXAMPLE 32
99mTc (chlorine)(dimethyl glyoxime).sub.3 2-phenylethyl boron
Following the procedure of example 2, but substituting 2-phenylethane boronic acid for boric acid, yielded the title complex.
EXAMPLE 33
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-(methoxymethyl)phenyl boron
Following the procedure of example 22, but substituting 1 mg of 4-(bromomethyl)benzene boronic acid for 3-(1-piperidinyl)propane boronic acid monohydrochloride and methanol for ethanol, yielded the title complex.
EXAMPLE 34
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-(butyloxymethyl)phenyl boron
Following the procedure of example 22, but substituting 1 mg of 4-(bromomethyl)benzene boronic acid for 3-(1-piperidinyl)propane boronic acid monohydrochloride and butanol for ethanol, yielded the title complex.
EXAMPLE 35 99mTc (chlorine)(1,2-cycloheptanedione dioxime).sub.3 methyl boron
Following the procedure of example 9, but substituting 1,2-cycloheptenedione dioxime for dimethyl glyoxime, yielded 92% of the title complex.
EXAMPLE 36
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-[(diethylamino)methyl]phenyl boron
Following the procedure of example 2, but substituting 4-[(diethylamino)methyl]benzene boronic acid monohydrochloride for boric acid, and adding 2.0 mg of diethylenetriamine pentacetic acid yielded 77% of the title complex.
EXAMPLE 37
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-(aminomethyl)phenyl boron
Following the procedure of example 2, but substituting 4-(aminomethyl)boronic acid monohydrochloride for 4-[(diethylamino)methyl]benzene boronic acid monohydrochloride, yielded 81% of the title complex.
EXAMPLE 38
99mTc (chlorine)(dimethyl glyoxime).sub.3 hexadecyl boron
Following the procedure of example 36, but substituting hexadecane boronic acid for 4-[(diethylamino)methyl]benzene boronic acid monohydrochloride, yielded the title complex.
EXAMPLE 39 99mTc (chlorine)(dimethyl glyoxime).sub.3 17-octadecenoic acid, 18-boron
Following the procedure of example 2, but substituting 18-borono-17-octadecenoic acid for boric acid, yielded 62% of the title complex.
EXAMPLE 40
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-formylphenyl boron
Following the procedure of example 2, but substituting p-(benzaldehyde)boronic acid for boric acid, yields 47% of the title complex.
EXAMPLE 41
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-[[methyl (2-phenylethyl)amino]methyl]phenyl boron
Following the procedure of example 2, but substituting 4-[[methyl(2-phenylethyl)amino]-methyl]benzene boronic acid monohydrochloride for boric acid, yielded the title complex.
EXAMPLE 42
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-ethylphenyl boron
Following the procedure of example 2, but substituting 4-ethylbenzene boronic acid for boric acid, yielded the title complex.
EXAMPLE 43
99mTc (chlorine)(dimethyl glyoxime).sub.3 2,4-dimethylphenyl boron
Following the procedure of example 2, but substituting 2,4-dimethylbenzene boronic acid for boric acid, yielded the title complex.
EXAMPLE 44
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-[(dimethylamino)methyl]phenyl boron
Following the procedure of example 2, but substituting 4-[(dimethylamino)methyl]benzene boronic acid monohydrochloride for boric acid, yielded the title complex.
EXAMPLE 45 99mTc (chlorine)(dimethyl glyoxime).sub.3 4-[(diisopropylamino)methyl]phenyl boron
Following the procedure of example 2, but substituting 4-[(diisopropylamino)methyl]benzene boronic acid monohydrochloride for boric acid, yielded the title complex.
EXAMPLE 46
99mTc (chlorine)(1,2-cyclohexanedionedioxime).sub.3 3-(1-piperidinyl)propyl boron
Into a 5 ml siliconized vial were measured 0.5 mg of 1,2-cyclohexanedione dioxime in 0.1 ml of ethanol, 1.0 mg of 3-(1-piperidinyl)propane boronic acid monohydrochloride, 0.2 ml of saturated sodium chloride, 10 mg of citric acid and 50.mu.l of saturated stannous pyrophosphate.
Sodium pertechnetate in physiological saline (0.2 ml) was added to the vial which was then heated at 100.degree. C. for 5 minutes yielding 84% of the title complex.
EXAMPLE 47 99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 3-(4-methyl-1-piperidinyl)propyl boron
Following the procedure of example 46, but substituting 3-(4-methyl-1-piperidinyl)propane boronic acid monohydrochloride for 3-(1-piperidinyl)propane boronic acid monohydrochloride, yielded 82% of the title complex.
EXAMPLE 48
99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 3-(4-morpholinyl)propyl boron
Following the procedure of example 46, but substituting 3-(4-morpholinyl)propane boronic acid monohydrochloride for 3-(1-piperidinyl)propane boronic acid monohydrochloride, yielded 90% of the title complex.
EXAMPLE 49
99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 3-aminophenyl boron
Following the procedure of example 46, but substituting 3-aminobenzene boronic acid monohydrochloride for 3-(1-piperidinyl)propane boronic acid monohydrochloride yielded 93% of the title complex.
EXAMPLE 50
99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 3-(4-phenyl-1-piperidinyl) propyl boron
Following the procedure of example 46, but substituting 5.0 mg of 3-(4-phenyl-1-piperidinyl)-propane boronic acid monohydrochloride for 3-(1-piperidinyl) boronic acid monohydrochloride and labeling with sodium pertechnetate in physiological saline (0.3 ml), yielded 84% of the title complex.
EXAMPLE 51
99mTc (bromime)(1,2-cyclohexanedione dioxime).sub.3 3-(4-phenyl-1-piperidinyl) propyl boron
Following the procedure of example 46, but substituting 5.0 mg of 3-(4-phenyl-1-piperidinyl)-propane boronic acid monohydrochloride for 3-(1-piperidinyl) propane boronic acid monohydrochloride and 100 mg of potassium bromide for sodium chloride yielded the title complex.
EXAMPLE 52
99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 1-butyl boron
Following the procedure of example 46, but substituting 1-butane boronic acid for 3-(piperidinyl)propane boronic acid monohydrochloride and labeling with sodium pertechnetate in physiological saline (0.3 ml) yielded 69% of the title complex.
EXAMPLE 53
99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 3-(5-dimethylamino-1-naphthalenesulfonylamino)phenyl boron
Following the procedure of example 46, but substituting 3-(5-dimethylamino-1-naphthalenesulfonylamino)benzene boronic acid for 3-(1-piperidinyl)propane boronic acid monohydrochloride and labeling with sodium pertechnetate in physiological saline (0.3 ml), yielded 80% of the title complex.
EXAMPLE 54
99mTc (chlorine)(1,2-ethanedione dioxime).sub.3 3-(5-dimethylamino-1-naphthalenesulfonylamino)phenyl boron
Following the procedure of example 53, but substituting 1,2-ethanedione dioxime for 1,2-cyclohexanedione dioxime, yielded 71% of the title compound.
EXAMPLE 55
99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 methyl boron
Into a 5 ml siliconized serum vial were measured 2.0 mg of 1,2-cyclohexanedione dioxime in 0.2 ml of ethanol, 2.0 mg of methane boronic acid, 10 mg of citric acid, 100 mg of sodium chloride, 1.0 mg of diethylenetriamine pentaacetic acid, and 50-60 .mu.g of anhydrous stannous chloride in 1.mu.l of concentrated hydrochloric acid.
Sodium pertechnetate in physiological saline (0.5 ml) was added to the vial which was then heated at 100.degree. C. for 5 minutes yielding 85% of the title complex.
EXAMPLE 56
99mTc (bromine)(1,2-cyclohexanedione dioxime).sub.3 methyl boron
Following the procedure of example 55, but substituting potassium bromide for sodium chloride and labeling with sodium pertechnetate in physiological saline (0.1 ml), yielded the title complex.
EXAMPLE 57
99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 4-ethylphenyl boron
Following the procedure of example 55, but substituting 4-ethylbenzene boronic acid for methane boronic acid, yielded the title complex.
EXAMPLE 58
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-[1-(diisopropylamino) ethyl]phenyl boron
Following the procedure of example 2, but substituting 4-[1-(diisopropylamino)ethyl] benzene boronic acid for boric acid, yielded the title complex.
EXAMPLE 59
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-[(isopropylamino) methyl]phenyl boron
Following the procedure of example 2, but substituting 4-[(isopropylamino)methyl]benzene boronic acid monohydrochloride for boric acid, yielded 8% of the title complex.
EXAMPLE 60
99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 4-methylphenyl boron
Following the procedure of example 2, but substituting 4-toluene boronic acid for boric acid and 1,2-cyclohexanedione dioxime for dimethyl glyoxime, yielded the title complex.
EXAMPLE 61
99mTc (chlorine)(dimethyl glyoxime).sub.3 2,4,6-trimethylphenyl boron
Following the procedure of example 2, but substituting 2,4,6-trimethylbenzene boronic acid for boric acid, yielded the title complex.
EXAMPLE 62
99mTc (chlorine)(dimethyl glyoxime).sub.3 2-methyl-1-propyl boron
Following the procedure of example 2, but substituting 2-methyl-1-propane boronic acid for boric acid, yielded 84% of the title complex.
EXAMPLE 63
99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 1-heptyl boron
Following the procedure of example 2, but substituting 1-heptane boronic acid for boric acid and 1,2-cyclohexanedione dioxime for dimethyl glyoxime, yielded the title complex.
EXAMPLE 64 99mTc (chlorine)(dimethyl glyoxime).sub.3 9-carboxynonyl boron
Following the procedure of example 2, but substituting 10-borono decanoic acid for boric acid, yielded the title complex.
EXAMPLE 65
99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 2-methyl-1-propyl boron
Following the procedure of example 2, but substituting 2-methyl-1-propane boronic acid for boric acid and 1,2-cyclohexanedione dioxime for dimethyl glyoxime, yield 85% of the title complex.
EXAMPLE 66
99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 ethyl boron
Following the procedure of example 2, but substituting ethane boronic acid for boric acid and 1,2-cyclohexanedione dioxime for dimethyl glyoxime, yielded 88% of the title complex.
EXAMPLE 67
99mTc (chlorine)(dimethyl glyoxime).sub.3 ethyl boron
Following the procedure of example 2, but substituting ethane boronic acid for boric acid, yielded 77% of the title complex.
EXAMPLE 68
99mTc (chlorine)(dimethyl glyoxime).sub.3 3-methylphenyl boron
Following the procedure of example 2, but substituting 3-toluene boronic acid for boric acid yielded the title complex.
EXAMPLE 69
99mTc (chlorine)(dimethyl glyoxime).sub.3 2-methylphenyl boron
Following the procedure of example 2, but substituting o-toluene boronic acid for boric acid yielded the title complex.
EXAMPLE 70
99mTc (chlorine)(dimethyl glyoxime).sub.3 cyclopentyl boron
Following the procedure of example 2, but substituting cyclopentane boronic acid for boric acid, yielded the title complex.
EXAMPLE 71
99mTc (chlorine)(dimethyl glyoxime).sub.3 2-butyl boron
Following the procedure of example 2, but substituting 2-butane boronic acid for boric acid, yielded the title complex.
EXAMPLE 72
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-methoxyphenyl boron
Following the procedure of example 2, but substituting 4-methoxybenzene boronic acid for boric acid, yielded the title complex.
EXAMPLE 73
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-(t-butyl)phenyl boron
Following the procedure of example 2, but substituting 4-(t-butane)benzene boronic acid for boric acid, yielded the title complex.
EXAMPLE 74
99mTc (chlorine)(1,2-ethanedione dioxime).sub.3 1-butyl boron
Following the procedure of example 2, but substituting 1-butane boronic acid for boric acid 1,2-ethanedione dioxime for dimethyl glyoxime yielded 76% of the title complex.
EXAMPLE 75
99mTc (chlorine)(dimethyl glyoxime).sub.3 4-(2-propyl)phenyl boron
Following the procedure of example 2, but substituting 4-(2-propane)benzene boronic acid for boric acid, yielded the title complex
EXAMPLE 76
99mTc (chlorine)(1,2-cyclohexanedione dioxime).sub.3 hydroxy boron
Following the procedure of example 2, but substituting 1,2-cyclohexanedione dioxime for dimethyl glyoxime, and omitting ethanol, yielded the title complex.
EXAMPLE 77
99mTc (chlorine)(.alpha.-furyldioxime).sub.3 methyl boron
Following the procedure of example 2, but substituting .alpha.-furyldioxime for dimethyl glyoxime, and methane boronic acid for boric acid, yielded the title complex.
EXAMPLE 78
99mTc (chlorine)(3-methyl-1,2-cyclopentanedione dioxime).sub.3 methyl boron
Following the procedure of example 2, but substituting 3-methyl-1,2-cyclopentanedione dioxime for dimethyl glyoxime and methane boronic acid for boric acid, yielded the title complex.
EXAMPLE 79
99mTc (chlorine)(1,2-cyclopentanedione dioxime).sub.3 methyl boron
Following the procedure of example 2, but substituting 1,2-cyclopentanedione dioxime for dimethyl glyoxime, and methane boronic acid for boric acid, yielded the title complex.
Claims
What is claimed is:
1. A boronic acid adduct of technetium-99m dioxime complexes having the formula wherein X is an anion; Y is a vicinal dioxime having the formula ##STR6## or a pharmaceutically acceptable salt thereof, wherein R.sub.1 and R.sub.2 are each independently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containing heterocycle, or together R.sub.1 and R.sub.2 are --(CR.sub.8 R.sub.9).sub.n --wherein n is 3, 4, 5 or 6 and R.sub.8 and R.sub.9 are each independently hydrogen or alkyl; and Z is a boron derivative of the formula wherein R.sub.3 is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R.sub.4 R.sub.5 N)-alkyl and R.sub.4 and R.sub.5 are each independently hydrogen, alkyl, or arylalkyl, or R.sub.4 and R.sub.5 when taken together with the nitrogen atom to which they are attached form a 5 or 6-membered nitrogen containing heterocycle.
2. A boronic acid adduct in accordance with claim 1, wherein X is a halide.
3. A boronic acid adduct in accordance with claim 1, wherein X is chloride or bromide.
4. A boronic acid adduct in accordance with claim 1, wherein X is chloride.
5. A boronic acid adduct in accordance with claim 1, wherein Y is dimethyl glyoxime, 1,2-cyclohexanedione dioxime, 1,2-ethanedione dioxime, .alpha.-furyldioxime, 1,2-cyclopentanedione dioxime, or 3-methyl-1,2-cyclopentanedione dioxime.
6. A boronic acid adduct in accordance with claim 1, wherein Y is dimethyl glyoxime
7. A boronic acid adduct in accordance with claim 1, wherein Y is 1,2-cyclohexanedione dioxime.
8. A boronic acid adduct in accordance with claim 1, wherein Y is 1,2-ethanedione dioxime.
9. A boronic acid adduct in accordance with claim 1, wherein Y is .alpha.-furyldioxime.
10. A boronic acid adduct in accordance with claim 1, wherein the boron derivative Z is B-alkyl.
11. A boronic acid adduct in accordance with claim 1, wherein the boron derivative Z is B-alkoxy.
12. A boronic acid adduct in accordance with claim 1, wherein the boron derivative Z is B-benzyl.
13. A boronic acid adduct in accordance with claim 1, wherein the boron derivative Z is B-cycloalkyl.
14. The boronic acid adduct in accordance with claim 1, 99mTc (chlorine) (1,2-cyclohexanedione dioxime).sub.3 methyl boron.
15. The boronic acid adduct in accordance with claim 1, 99mTc (chlorine)(dimethyl glyoxime).sub.3 1-methylpropyl boron.
16. The boronic acid adduct in accordance with claim 1, 99mTc (chlorine)(dimethyl glyoxime).sub.3 4-methylphenyl boron.
17. The boronic acid adduct in accordance with claim 1, 99mTc (chlorine)(dimethyl glyoxime).sub.3 cyclopentyl boron.
18. The boronic acid adduct in accordance with claim 1, 99mTc (chlorine) 1,2-cyclohexanedione dioxime).sub.3 ethyl boron.
19. The boronic acid adduct in accordance with claim 1, 99mTc (chlorine)(dimethyl glyoxime).sub.3 4-(t-butyl)phenyl boron.
20. The boronic acid adduct in accordance with claim 1, 99mTc (chlorine) (dimethyl glyoxime).sub.3 2-methyl-1-propyl boron.
21. The boronic acid adduct in accordance with claim 1, 99mTc (chlorine) (1,2-cyclohexanedione dioxime).sub.3 hydroxy boron.
22. A kit suitable for labeling with technetium-99m, said kit comprising: (i) a source of anion; (ii) a boronic acid derivative, or compounds which can react in situ to form a boronic acid derivative, having the formula ##STR7## or a pharmaceutically acceptable salt thereof, wherein R.sub.3 is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxy-alkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl, or R.sub.4 R.sub.5 N-alkyl and R.sub.4 and R.sub.5 are each independently hydrogen, alkyl, or arylalkyl, or R.sub.4 and R.sub.5 when taken together with nitrogen atom to which they are attached form a 5 or 6-membered nitrogen containing heterocycle, and R.sub.7 is hydrogen, alkyl or aryl; (iii) a dioxime having the formula ##STR8## or a pharmaceutically acceptable salt thereof, wherein R.sub.1 and R.sub.2 are each independently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containing heterocycle, or together R.sub.1 and R.sub.2 are --(CR.sub.8 R.sub.9).sub.n --wherein n is 3, 4, 5 or 6 and R.sub.8 and R.sub.9 are each independently hydrogen or alkyl; and (iv) a reducing agent.
23. A kit in accordance with claim 22, wherein the source of anion is a source of halide.
24. A kit in accordance with claim 22, wherein the source of anion is a source of chloride or bromide.
25. A kit in accordance with claim 22 wherein the dioxime is dimethyl glyoxime, 1,2-cyclohexanedione dioxime, 1,2-ethanedione dioxime or .alpha.-furyldioxime.
26. A kit in accordance with claim 22, wherein the dioxime is dimethyl glyoxime.
27. A kit in accordance with claim 22, wherein the dioxime is 1,2-cyclohexanedione dioxime.
28. A kit in accordance with claim 22, wherein the reducing agent is a stannous salt.
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