Bis-H-phosphinic acid derivatives as precursors to...

Details Bis-H-phosphinic acid derivatives as precursors to... Bis-H-phosphinic acid derivatives as precursors to...

2002-12-13

2004-08-24

Vollano, Jean F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Phosphorus acids or salts thereof

C562S008000

Reexamination Certificate

active

06781011

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Funding Legend
This invention was produced in part using funds through grant No. P-1435 from the Robert A. Welch Foundation.
2. Field of the Invention
The present invention relates generally to the field of chemistry and drug therapy. More particularly, the present invention provides novel bis-H-phosphinic acid derivatives and methods of producing bis-H-phosphinic acid derivatives. The present invention also provides methods of producing drug or protein conjugates using bis-H-phosphinic acid derivatives and methods of treating bone-related and various other diseases using such derivatives or conjugates.
3. Description of Related Art
Bisphosphonates are used to target molecules to the bone. Pharmaceutical compounds derived from bisphosphonates are used to treat bone cancer, bone infection or deliver steroids to the bone to treat osteoporosis. Bisphosphonates are not only important drugs for the treatment of bone-related diseases, but also important drugs for various other diseases such as high cholesterol. They are currently $1 billion market worldwide. Although they are generally 1-hydroxy-substituted, these compounds have a major limitation. That is, they display poor oral bioavailability because most of the compounds are excreted. Also high dosage causes serious side effects.
Several pharmaceutical companies have been trying to modify bisphosphonates to improve their biological activities. The approach commonly used is to mask the charge of the phosphonate to increase penetration through membranes. However, extensive manipulation is required to modify bisphosphonates which have 3-4 charges at physiological pH.
Bisphosphinates (or phosphinic acid derivatives) are precursors to bisphosphonates. Presently, bisphosphinates oxidize into corresponding bisphosphonates by cumbersome multistep synthesis. Bisphosphinates have been prepared under radial conditions. For example, Nifant'ev (
J. Gen. Chem. USSR
1986, 56, 680) taught reacting sodium hypophosphite or hypophosphorous acid with alkynes in the presence of peroxides and extensive heat to prepare biophosphinates. Low yields of 1,2-bis-H-phosphinates were sometime obtained from Nifant'ev's method.
Therefore, there is an increasing need for a simple, expeditious and effective method for synthesizing bisphosphonates with increased bioavailability.
SUMMARY OF THE INVENTION
With the foregoing in mind, the present invention provides a novel class of compounds, i.e., 1,1-bis-H-phosphinates (or 1,1-bis-H-phosphinic acid derivatives). Also, the present invention provides a novel method for producing 1,1-bis-H-phosphinates. These compounds are used as precursors of bisphosphonates through chemical or in vivo biological oxidation.
In one embodiment of the present invention, there is provided a 1,1 -bis-H-phosphinate compound having a structure of
In the structure, R includes Na, H, PhNH3 and alkyl, and R′ includes alkyl, COOH, NH
2
, epoxide, OH, CHO, SH, CH
2
NH
2
, CH
2
COO-steroid, CH
2
-famesyl, CH
2
-geranyl, N-fluoroquinolones, CH
2
S-albumin and NMe
2
CF
2
COOH. Preferably, this compound is a 1,1-bis-H-phosphinate.
In another embodiment of the present invention, there is provided a method for producing a bis-H-phosphinate compound. In this method, a hypophosphorous derivative reacts with an alkyne in the presence of a radical initiator at ambient temperature and pressure conditions. The reaction can be carried out, for example, at room temperature in an open container. Preferably, the radical initiator is an organoborane catalyst, for example, triethylborane.
In still another embodiment of the present invention, there is provided a method for producing a bis-H-phosphinate conjugate. In this method, a hypophosphorous derivative first reacts with an alkyne in the presence of a radical initiator at room temperature in an open container to produce a bis-H-phosphinate compound. The bis-H-phosphinate then reacts with a compound having a pendant functional group to produce a bis-H-phosphinate conjugate. Preferably, the compound having a pendant functional group is a pharmaceutical compound or a protein. An example of the functional group is an alkyne group.
In yet another embodiment of the present invention, there is provided a method for treating an individual having a bone-related disease by administering to the individual an effective dose of a bis-H-phosphinate compound or a bis-H-phosphinate conjugate. Same compound or conjugate can also be used for treating an individual having high cholesterol.


REFERENCES:
patent: 3366678 (1968-01-01), Guttman et al.
patent: 5194581 (1993-03-01), Leong
patent: 5712261 (1998-01-01), Magnin et al.
patent: 6238687 (2001-05-01), Mao et al.
patent: 6278012 (2001-08-01), Hörold et al.
CA:137:47314 abs of EP 1217004 Jun. 26, 2002.*
CA:108:137664 abs of CN86105761.*
CA:108:16755 abs of Zhurnal Obshchei Khimii by Novikova et al 57(3) pp 525-533 1987.*
CA:111:11554 abs of Dissertation Abstr Int B by C. King 49 (8) pp 3181 1988.*
CA:104:168573 abs of Inorganic Chem byKing et al 25 (8) pp 1290-1292 1986.*
Nifant'ev, Reactions of Acetylenes With Hypophosphorous and Phosphonous Acids, 1986 Plenum Publishing Corporation, article submitted Apr. 23, 1985.
Major, et al, Oral Bisphosphonates, A Review of Clinical Use in Patients with Bone Metastases, Apr. 16, 1999, 2000 American Cancer Society.
Martin et al; Activity of Bisphosphonates against Trypanosoma brucei rhodesiense, J. Med. Chem. 2002, 2904-2914, Jun. 20, 2001.
Szabo et al; An Investigation of Bone Resorption and Dictyostelium discoideum Growth Inhibition by Bisphosphonate Drugs; J. Med. Chem. 2002, 45, 2894-2903; Jun. 20, 2001.
Deprèle et al; Triethylborane-Initiated Room Temperature Radical Addition of Hypophosphites to Olefins: Synthesis of Monosubstituted Phosphinic acids and Esters; Texas Christian University, Jun. 28, 2001.

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