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Title:
MULTIFUNCTIONAL LIGAND FOR USE AS A DIAGNOSTIC OR THERAPEUTIC PHARMACEUTICAL
Document Type and Number:
WIPO Patent Application WO/1992/019235
Kind Code:
A2
Abstract:
A compound and method of making a compound for use as a diagnostic or therapeutic pharmaceutical comprises either a phosphorous or germanium core and at least two hydrazine groups forming a ligand for bonding to a metal extending from the phosphorous or germanium core.

Inventors:
Katti, Kattesh V.
Volkert, Wynn Arthur Ketring Alan Reed
Application Number:
PCT/US1992/003247
Publication Date:
November 12, 1992
Filing Date:
April 21, 1992
Export Citation:
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Assignee:
THE CURATORS OF THE UNIVERSITY OF MISSOURI.
International Classes:
A61K51/04; C07F7/00; C07F7/30; C07F9/06; C07F9/22; C07F9/44; C07F9/535; C07F13/00; C07F15/00; C07F15/06; C07F19/00; (IPC1-7): A61K31/135; A61K31/15; A61K31/66; A61K31/675; A61K31/695; C07D241/02; C07F7/10; C07F7/30; C07F9/50; C07F9/53; C07F13/05; C07F15/02; C07F15/06; C09K3/00
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Claims:
What is claimed:
1. A compound for use as a diagnostic or therapeutic pharmaceutical, or MRI contrast agent said compound comprising: a phosphine core, and at least two hydrazine groups forming a ligand for binding to a metal extending from said phosphorous core.
2. A compound as set forth in claim 1 wherein said ligand is a bishydrazine phosphine.
3. A compound wherein said ligand is of the for ul a: R^ Rj;, Rj, R4, are all the same or different and are H, alkyl (Me, Et, n or i propyl, n, or i butyl, n or cyclohexyl) alkylamine (primary and secondary) ; NMe2, NHMe, (CH2)_NMe2, (CH2)_NHMe,(CH2)_NH2; alkoxy (0(CH2)nCH3 or (CH2)nOCH3; aromatics, C6H5R wherein R = H, NH2, COOH, NCS, CHO, activated esters, acid anhydrides, Nhydroxy succinamide, and SiMe3, R5 = H; Me, Ph. E = 0, S, NSiMe3, a lone pair of electrons; NC6H4R:R=H, NH2, COOH, NCS, CHO, Nhydroxy succinamide, activated esters or acid anhydrides.
4. A compound as set forth in claim 1 wherein said ligand is a trishydrazine phosphine.
5. A compound as set forth in claim 4 wherein said ligand is of the formula: R1, Rj, Rj, R4, are all the same or different and are H, alkyl (Me, Et, n or i propyl, n, or i butyl, n or cyclohexyl) alkyla ine (primary and secondary) ; NMe2, NHMe, (CH2)nNMe2, (CH2)nNHMe,(CH2).NH2; alkoxy (0(CH2)nCH3 or (CH2)nOCH3; aromatics, C6HjR wherein R = H, NH2, COOH, NCS, CHO, activated esters, acid anhydrides, Nhydroxy succinamide, and SiMe3, R5,R6 = H; Me, Ph. E = O, S, NSiMe3, a lone pair of electrons; NC6H4R:R=H, NH2, COOH, NCS, CHO, Nhydroxy succinamide, activated esters or acid anhydrides.
6. A compound as set forth in claims 3 or 5 wherein said ligand is complexed with a transition metal.
7. A compound as set forth in claim 6 wherein said transition metal is a radionuclide selected from the group including 186Re, 188Re, 109Pd, 105Rh and "Tc, said compound being stable in aqueous solutions, serum and other body fluids.
8. A compound as set forth in claim 7 wherein said transition metal is a paramagnetic transition metal selected from the group includes Fe or Mn, said compound being stable in aqueous solutions, serum or other body fluids.
9. A compound as set forth in claims 7 or 8 including a 1:1 metal to liqand ratio.
10. A compound as set forth in claims 3 or 5 wherein said ligand is conjugated to a protein or antibody.
11. A compound as set forth in claim 10 wherein any one or several of R1, R2, R3, R4, R5, or R6 are benzyl isocyanate, bromacetamide, an activated ester, Nhydroxysuccinimides, a cleavable ester or an aldehyde.
12. A compound as set forth in claims 3 or 5 wherein any one or all of R1, R2, R3, R4, R5, or R6 are carboxylated or hydroxylated to render said ligand more polar.
13. Compounds for use as diagnostic or therapeutic pharmaceuticals or MRI contrast agents, said compounds comprising a germanium core, and at least two hydrazine groups forming ligands for binding to a mutal extending from said germanium core.
14. Compounds as set forth in claim 13 wherein said ligands are bis, tris or tetra hydrazine germanium ligands.
15. Compounds wherein ligands are of the formula: R R2, R3, R4, are all but the same or different and are H, alkyl (Me, Et, n or i propyl, n, or i butyl, n or cyclohexyl) alkylamine (primary and secondary) ; NMe2, NHMe, (CH2)nNMe2, (CH2).NHMe, (CH2)nNH2; alkoxy (0(CH2)nCH3 or (CH2)nOCH3); aromatics, CH6H5R wherein R = H, NH2, COOH, NCS, CHO, activated esters, acid anhydrides, Nhydroxy succinamide, and SiMe3, R5, R6 = Cl, Me, Ph or R1NNH2 NC6H4R; R = H, NH2, Cooh, NCS, CHO, Nhydroxy succinamide, activated esters or acid anhydrides; are all the same or different.
16. A method of making a compound for use as a diagnostic or therapeutic pharmaceutical, said method including the following reaction: Cl R » N ~— \r E=P Cl \ X H _ N .3 R5 R6 / / wherein R1 = H; X is NNH, alkyl, (Me, Et, nor i propyl, n, ior tbutyl, n and cyclohexyl) , alkyl amine (primary and secondary) ,NMe2, MHMe, (CH2)n NMe2, (CH2)n NHMe, (CH2)nNH2, alkoxy [0(CH2)2nCH3)n] , aromatics (C6 H4R7 wherein R7 is H, NH2 COOH, NCS, CHO, activated esters, acid anhydrides, (Nhydroxy succinimide, and SiMe3. R2, R3, R4, R6 are all the same or different being H, alkyl (Me, Et, nor i propyl, n, ior tbutyl, nand cyclohexyl) , alkyl amine, primary and secondary [NMe2, NHMe, (CH_)nNMe2 (CH2)nNHMe, (CH2)nNH2], alkyoxy [0 (CH2)n CH3 or (CHg),, 0CH3] . R5 is the same or different than R2, R3, R4, R6 and is all the substitutes defined for X accept for the hydrazine group. E is 0, S, NSiMEj, a lone pair of electrons, NC6H4R8,R8 = H, NH2, C00H, NCS, CHO, Nhydroxysuccinimide, activated esters or acid anhydrides.
17. A method as set forth in claim 18 further including the step of chelating the compound to a transition metal selected from the group including Fe, Mn 186Re, 188Re, 10Pd, 105Rh and "Tc, 5 said compound being stable in aqueous solutions, serum and other body fluids.
18. A method as set forth in claim 16 wherein said compound is conjugated to a protein or 10 antibody.
19. A method as set forth in claim 18 further including the step of derivatizing R1, R2, R3, R5, or R6, to a benzyl isocyanate, 15 bromoacetamide, activated ester, N hydroxysuccinimide, cleavable ester, or aldehydes.
20. A method as set forth in claim 16 further including the step of modifying R1, R2, R3, 20 R5, or R6, to be more polar, thereby rendering the compound more hydrophilic.
21. A method as set forth in claim 20 wherein said modifying step is further defined or 25 hydroxylating or carboxylating R1, R2, R3, R5, or R6.
Description:
MϋLTIFUNCTIONAL LIGAND FOR USE AS A DIAGNOSTIC OR THERAPEUTIC PHARMACEUTICAL

TECHNICAL FIELD

The present invention relates to pharmaceuticals, and especially radiopharmaceuticals for use as diagnostic and therapeutic agents. More specifically, the present invention relates to a compound and method of synthesizing a compound which is a multidentate ligand that complexes with transition metal radionuclides for use as diagnostic or therapeutic radiopharmaceuticals.

BACKGROUND OF THE INVENTION

Radiotherapy using "non-sealed sources" by way of radiolabeled pharmaceuticals has been employed for several decades (1-3) .

Unfortunately, less than a handful of therapeutic radiopharmaceuticals are currently in routine use, as being approved by the FDA. There has been renewed interest in developing new agents due to the emergence of more sophisticated molecular carriers, such as monoclonal antibodies

that are capable of selectively targeting cancerous lesions. In addition, the identification of several different radionuclides (4-7) with different chemical properties that have physical decay properties that are desirable for therapeutic application have further spurred development of new agents.

Despite some successes in treatment of specific malignant diseases and increased research and development activities in this area, many problems remain with the use of such treatments. For example, in most cancers, it has been difficult to provide acceptable selectivity in radiation doses delivered to target tissues relative to normal tissues. Successful development of new therapeutic radiopharmaceuticals requires improved localization of these agents in target tissues and/or increasing rates of clearance from non- target tissues. In both of these cases, it is imperative that the therapeutic radionuclide remain firmly associated with the radioactive drug in vivo for extended periods of time. These periods of time can extend from a few hours up to several days, depending on the pharmacokinetics and physical half-life of the radionuclide. No

single radionuclide can be appropriate in formulating therapeutic agents since different half-lives and the energy of emitted particles is required for different applications (4-7) thereby making it essential that radiopharmaceuticals with different radionuclides be available.

Therapeutic agents have been primarily labeled with beta-particle emitting radionuclides. Most of the promising radionuclides are produced in nuclear reactors, however, some are accelerator produced (4-7) . Several different chelating structures have been employed to maintain the association of these beta emitters with the drug (8-12) . Many of these structures are not sufficiently stable and most, if not all, do not provide appropriate routes or rates of clearance of radioactivity from non-target tissues (13-14) . Accordingly, there is a delivery of high radiation doses to normal tissues and a reduction of the therapeutic ratio. This lowers the amount of radiation dose that can be safely delivered to a target tissue. Development of new radionuclide chelates that link the radioactive metal to the radiopharmaceutical is necessary. Further, new approaches must be taken in order to identify

radio-labeling techniques that produce chelates that are highly stable in vivo but have improved clearance characteristics from normal tissues. Bi-functional chelating agents have been used to form stable metal complexes that were designed to minimize in vivo release of the metallic radionuclide from the radiopharmaceutical. For example, diethyltriaminepentaacetic acid (DTPA) forms rather stable chelates with a variety of metals. However, coupling of this ligand to monoclonal antibodies by one of its five carboxyl groups resulted in unacceptable in vivo stability with a variety of radionuclides (15) . Linking of this compound by a side group attached to one of the carbon atoms on an ethylene bridging group provides improved stability n vitro and in vivo. The stability characteristics of these compounds are not ideal resulting in poor clearance of activity from certain non-target organs are poor.

Chelating agents based on diamido- dithiol and triamidomonothiol backbones are used for forming small and stable hydrophilic complexes with several beta-emitting transition metals. These were developed by Fritzberg and colleagues (10) for labeled monoclonal antibody

products for diagnostic and therapeutic applications. These chelates provide improved clearance characteristics from the liver, however, kidney retention of activity when using Fab or (Fab) 2 fragments of monoclonal antibodies labeled with these radionuclide chelates is higher than desirable.

A macrocyclic tetramine-based chelating agent that also has four methylene carboxylate side atoms has been used to form a copper complex that has a high in vitro and in vivo stability when linked to monoclonal antibodies. This chelate was first described for monoclonal antibody bioconjugation by Meares and coworkers (11,12). The chelate is rather large. Clearance of activity from non-target organs has not been shown to be more efficient than the chelates mentioned above.

Recently, a mono-hydrazide bifunctional chelating agent has been described that forms somewhat stable "Tc complexes (16,17). This particular ligand can be first attached to a protein and then binds to ""Tc as it is chelated with glucoheptonate in aqueous solutions at or near neutral pH (17) . Other work with mono- hydrazide ligands with other Tc v complexes

demonstrates the reaction of the monohydrazides at the axial position with Tc v =0 to form similar mondentate linkages (16) . The in vitro and in vivo stability of these types of chelates has not been adequately described in the literature.

Applicant has synthesized a series of multi-dentate ligands derived from a phosphorous or germanium core utilizing hydrazine groups as arms of these ligands to form small but stable and well defined complexes with transition metal radionuclides. Unlike prior art chelates, these chelates show good stability in both aqueous solutions, serum, and other body fluids.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a compound for use as a diagnostic or therapeutic pharmaceutical, the compound comprising a phosphorous or germanium core and at least two hydrazine groups forming a ligand for bonding to a metal extending from the phosphorous or germanium core.

The present invention further provides a method of making the compound for use as a

diagnostic therapeutic pharmaceutical, the method including the following reaction

Cl

/

E=P— Cl

\ X

R 5 R 6 / Wherein R, = H; X is N-N-H, alkyl, (Me, Et, n-or i - propyl, n-, i-or t-butyl, n and cyclohexyl) , alkyl a ine (primary and secondary) ,-NMe 2 , MHMe, - (CH 2 ) n NMe 2 ,- (CH 2 ) n NHMe, -(CH 2 )_NH 2 , alkoxy [0(CH 2 ) 2n CH 3 ) n ] , aromatics (-C 6 H 4 R 7 wherein R 7 is H, NH 2 COOH, NCS, CHO, activated esters, .acid anhydrides, (N-hydroxy succinimide, and SiMe 3 . R 2 ' R 3 , R 4 , R 6 are all the same or different being H, alkyl (Me, Et, n-or i- propyl, n-, i-or t-butyl, n-and cyclohexyl) , alkyl amine, primary and secondary [-NMe 2 , NHMe, - (CH 2 ) n NMe 2 - (CH 2 ) n NHMe, - (CH 2 ) n NH 2 ], alkyoxy [0 (CH 2 ) n CH 3 or - (CH 2 ) n 0CH 3 ] . R 5 is the same or different than R 2 , R 3 , R 4 , R 6 and is all the substitutes defined for X accept for the hydrazine group. E is 0, S,

NSiME j , a lone pair of electrons, NC 6 H 4 R 8 ,R 8 = H, NH-,

CooH, NCS, CHO, N-hydroxysuccinimide, activated esters or acid anhydrides.

Similar reactions of germanium halides (eg., GeCl 4 , RGeCl 3 ) with hydrazine reactants as defined above for the phosphorous core produced germanium hydrazides containing up to four hydrazine units.

DETAILED DESCRIPTION OF THE INVENTION

Generally, the present invention provides a compound for use as a diagnostic or therapeutic pharmaceutical however, they may also be used for other pharmaceutical applications including MRI contrast agents. The compound includes a phosphine core and at least two hydrazine groups forming a ligand for bonding to a metal extending from the phosphorous or germanium core. That is, the invention provides phosphorous and germanium hydrazide ligand systems containing between 2 and 4 hydrazine units for use in forming complexes with a variety of transition metals that have high is vitro and/or in vivo stability.

The phosphorous and germanium ligands were chosen since the hydrazine arms linked directly to phosphorous atom provides a plethora of electron

density on the terminal hydrazine-N-atoms that promote formation of highly stable nitrogen-metal bonds. This occurs even with the transition metals in their higher oxidation states, such as Re . The utilization of at least two hydrazine groups for metal bonding produces complexes that are more stable than the metal complexes with only one hydrazine arm.

The ligand is complexed with the transition metal, generally from the group including Fe, Mn, Re, Re, Pd, Rh, and 99m Tc. These complexes contain a 1:1 metal to ligand ratio which is formed making the resulting chelates small and well- defined. These specific combinations permit the formation of the complexes in a one step, high yield reaction as described below, especially for use with readily available chemical forms of the radionuclides.

For example, ""TcO " , ReO chelates or PdCl 2 can be used. It has been determined that these types of ligands form highly stable chelates with a variety of transition metals that have radioactive isotopes that have potential for formulation of new therapeutic uses, such as 186 Re, 188 Re, 109 Pd, 105 Rh, etc. , or for diagnostic use such as with "Tc radiopharmaceuticals.

For example, Fe and Mn are paramagnetic elements and have potential application in chelate form as MRI contrast imaging agents. Stable Mn and Fe chelates with the P and Ge hydrazine ligands with appropriate substituents can be formulated.

The chelates made in accordance with the present invention have been found to be stable in aqueous solutions, serum and other body fluids. This is critical to solve the problems of prior art agents which did not form stable chelates thereby having an inherent loss of control of localization of the radionuclide paramagnetic metal. Further, compounds made in accordance with the present invention can be chemically modified, as discussed below, to provide for specificity of localization, increased physical half-life of the radionuclide, improved pharmacokinetics , and increased selectivity of target tissues, such as tumors, over normal tissue, such as bone marrow, kidney, GI tract, liver etc.

The compounds made in accordance with the present invention are not only stable in neutral aqueous solutions, but have also been found to be stable in acidic and basic aqueous media. Again, this is critical with regard to localization of the compound in areas of the body having different pH's,

-li¬

as well as being stable through different administration routes, such as oral administration.

More specifically, the bis-hydrazine ligand made in accordance with the present invention can characterized by the following formula:

H

R R 2 , R 3 , R 4 , are all the same or different and are H, alkyl'(Me, Et, n or i propyl, n, or i butyl, n or cyclohexyl) alkyla ine (primary and secondary) ; - NMe 2 , NHMe, (CH 2 ).NMe 2 , (CH 2 ) n NHMe,-(CH 2 ) n NH 2 ; alkoxy (-0(CH 2 ) n CH 3 or (CH 2 ) n OCH 3 ; aromatics, C 6 H 5 R wherein R = H, NH 2 , COOH, NCS, CHO, activated esters, acid anhydrides, N-hydroxy succinamide, and SiMe 3 , R 5 = H; Me, Ph, E = 0, S, -NSiMe 3 , a lone pair of electrons; NC 6 H 4 R:R = H, NH 2 , COOH, NCS, CHO, N-hydroxy succinamide, activated esters or acid anhydrides.

The tris-hydrazine ligand made in accordance with the present invention can be characterized by the following:

H H

R 1f R 2 , R j , R 4 , are all the same or different and are H, alkyl (Me, Et, n or i propyl, n, or i butyl, n or cyclohexyl) alkylamine (primary and secondary) ; - NMe 2 , NHMe, (CH 2 ) n NMe 2 , (CH 2 ) n NHMe, -(CH 2 ) n NH 2 ; alkoxy (-0(CH 2 ) n CH 3 or (CH 2 ) n OCH 3 ; aromatics, C 6 H 5 R wherein R = H, NH 2 , COOH, NCS, CHO, activated esters, acid anhydrides, N-hydroxy succinamide, and SiMe 3 , R 5 R 6 = H; Me, Ph. E = 0, S, -NSiMe^, a lone pair of electrons; NC 6 H 4 R:R - H, NH 2 , COOH, NCS, CHO, N- hydroxy succinamide, activated esters or acid anhydrides. The germanium hydrazide ligands made in accordance with the present invention can be characterized by the following:

R 1# R-,, R 3 , R 4 , are all the same or different and are H, alkyl (Me, Et, n or i propyl, n, or i butyl, n or cyclohexyl) alkylamine (primary and secondary) ; - NMe 2 , NHMe, (CH 2 ).NMe 2 , (CH 2 ).NHMe, -(CH 2 ) n NH 2 ; alkoxy (-0(CH 2 ) n CH 3 or (CH 2 ) n OCH 3 ; aromatics, C 6 H 5 R wherein R= H, NH 2 , COOH, NCS, CHO, activated esters, acid anhydrides, N-hydroxy succinamide, and SiMe 3 , R 5 R 6 = Cl, Me, Ph or R.N-NH j NC 6 H 4 R; R = H, NH 2 , CooH, NCS, CHO, N-hydroxy succinamide, activated esters or acid anhydrides are all the. same or different.

The above formulas characterize the present invention as being very modifiable in order to specifically tailor the ligand for chelation with a specific radionuclide and localization at a specific target organ.

For example, the ligand can be conjugated to protein or antibodies and can use side chains previously used for linking monoclonal antibodies (15) . For example, conjugation reactions can involve reactive groups such as benzyl isothiocyanate, bromoacetamide, activated esters, N- hydroxysuccinimides, cleavable ester linkages, and aldehydes (15) . In the case where E is a lone pair of electrons on the phosphorous atom, attachment of the chelate or the hydrazide ligand to proteins or other molecules already containing an azido group

can be brought about by the standinger reaction. The conjugation reaction can occur using any of the R groups attached to the nitrogens on one of the hydrazine side arms or attached directly to the phosphorous or germanium atom. Accordingly, a single monoclonal antibody or several monoclonal antibodies can be added to the phosphorous or germanium hydrazine core to provide specificity of the binding of the ligand metal complex to specific surface antigen of target tissue.

As discussed above, other side chain modifications can be accomplished to make the chelate more polar and hydrophilic. For example, charged groups such as carboxyl or hydroxyl groups can be added at -the various R groups appended to the hydrazine nitrogens. This additional small change in the compounds providing charged/polar groups increases the hydrophilic character of the resulting chelate. This will produce more rapid and selective clearance from the blood and nontarget tissue. This modification is highly desirable for the promotion of efficient clearance of radioactivity from nontarget tissues, such as blood, liver, kidney, and spleen following catabolism of conjugated radiolabeled monoclonal antibodies that are presently used for therapy.

Alternatively, the hydrophobicity of the chelate can be varied incrementally by varying the alkyl chain length of the side chains appended to the hydrazine nitrogens. For example, the R groups or the hydrazine side arms can be derivatized with hydrogen, methyl, ethyl, n-, or -i-propyl or ni-, or t-butyl. This is desirable because with some chelates, particularly those labeled with "Tc, an increase in the hydrophobicity of the chelate plays a major, role in targeting uptake in selective tissues, such as in brain, heart and lung. Addition of alkyl groups to the chelating backbone increases the lipid solubility of the chelate. If the resulting chelate is neutral, either brain, heart, or lung imaging agents can be developed (18) . Similarly, if the overall chelate charge is +1 myocardial imaging agents can be developed (19) . Modifying the hydrophobicity of chelates with beta- emitting radionuclides for therapy will also change the clearance and uptake properties in target and nontarget tissues.

An alternative to varying the alkyl chain length of the R groups appended to the nitrogens of the hydrazines is to add other hydrophobic functional groups, such as alkyl methoxy and alkyl methoxys to the R groups. The use of ether side

chains instead of the alkyl side chains will increase lipophilicity but also improves the rate of clearance of the chelate from the blood and other non-target tissues. Other side chain modifications to increase hydrophilicity, such as the addition ester groups or amide groups, can also be accomplished.

Another alternative modification of the chelate is to modify the charge or basic metal chelate core. It is possible to make the chelate with zero charge to produce a neutral hydrophilic chelate. For example, the bis-hydrazine ligand can be modified by the addition of a side chain other than hydrogen at the R groups attached to one of the hydrazine terminal nitrogens. Alternatively, negatively charged groups can be added, such as (-CH 2 )_-SH or(-CH 2 ) n -C00H.

All of the aforementioned modifications demonstrate the flexibility of compounds made in accordance with the present invention and further the ability to modify these compounds to alter the binding, elimination, and absorption of the compounds in order to tailor the compounds for specific organ targeting, dosing, and metabolism. Compounds made in accordance with the present invention for use as diagnostic or

therapeutic pharmaceuticals can be made by the following general reaction:

Cl s

E=P- Cl \ X

wherein R, = H; X is N-N-H, alkyl, (Me, Et, n-or i - propyl, n-, i-or t-butyl, n and cyclohexyl) , alkyl amine (primary and secondary) ,-NMe 2 , MHMe, - (CH 2 ) n NMe 2 ,- (CH 2 ) n NHMe, -(CH 2 ) n NH 2 , alkoxy [0(CH 2 ) 2 .CH 3 ) n ] , aromatics (-C 6 H 4 R 7 wherein R 7 is H, NH 2 COOH, NCS, CHO, activated esters, acid anhydrides, (N-hydroxy succinimide, and SiMe 3 . R 2 ' R 3 , R 4 , R 6 are all the same or different being H, alkyl (Me, Et, n-or i- propyl, n-, i-or t-butyl, n-and cyclohexyl) , alkyl amine, primary and secondary [-NMe 2 , NHMe, - (CH 2 ) n NMe 2 - (CH 2 ) n NHMe, - (CH 2 ) n NH 2 ], alkyoxy [O (CH 2 ) n CH 3 or - (CH 2 ) n OCH 3 ]. R 5 is the same or different than R 2 , R 3 , R 4 , R 6 and is all the substitutes defined for X accept for the hydrazine group. E is O, S, NSiME 3 , a lone pair of electrons, NC 6 H 4 R 8 ,R 8 = H, NH 2 , CooH, NCS, CHO, N-hydroxysuccinimide, activated esters or acid anhydrides.

A solution of the appropriate phosphorous halide (e.g. P(0)C1 3 , P(S)C1 3 , PC1 3 ; RPC1 2 R=Ph,Me...) in THF, toluene or chloroform was mixed with the solutions of lithiated or silyated hydrazines according to a set stoichio etry at 25°C. The reaction mixture was stirred at RT for 8-16 hours before the solvent was removed in the vacuum. The purifications of the phosphorous hydrazides were achieved either by recrystallization or through distillation under reduced pressure.

A solution of GeCl 4 or RGeCl 3 (R=Me,PH) in THF, toluene or CHC1 3 was mixed with the solutions of lithiated or silyated hydrazines according to a set stoichiometry at 25°C. The reaction mixtures were stirred at RT for 8-16 hour before the solvent was removed in vacuum. The germanium hydrazides were purified either by recrystallization or through distillations at reduced pressure.

The following are examples of ligands and chelates formed in accordance with the present invention.

EXAMPLE 1 Ligands Synthesized

1 2

Rj = R2 = R 3 = R 4 = H ; R χ = R 4 = Me

E = O, S, NSiMe 3 or electron pair

R = C1; NMe — NH 2 ; Ph; Me

EXAMPLE II Formation of Complexes with Rehenium

Re-BHP Complexes foπned:

Complex 1^ )

Characterized by *H and 31 P NMR and Q*N elemental analysis

b. Cpd E . J ; 1 H, 31 P NMR C.H . N EL AnaL

Formation of THP complexes with Re.

OSiMe 3

d. Formation of BHP complexes with Re

CpdlV^ j , l H, 31 PNMR C,H,NELAnal

The invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation.

Obviously many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.