Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus acids or salts thereof
Patent
1992-09-16
1994-07-05
Dees, Joee G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus acids or salts thereof
562 15, C07F 944
Patent
active
053269055
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to acid compounds which are useful in the field of medicinal chemistry. More particularly the invention relates to benzylphosphonic acid compounds which are tyrosine kinase inhibitors useful for the control of cancer, antiangiogenesis and atherosclerosis.
BACKGROUND OF THE INVENTION
Tyrosine-specific protein kinases (tyrosine kinases) represent a family of enzymes which catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. The first members of this class to be identified were tyrosine kinases associated with viral genes (termed oncogenes) which were capable of cell transformation (i.e. pp60v-src and pp98v-fps). Later it was shown that there were normal cellular counterparts (i.e. pp60c-src and pp98c-fps) to these viral gene products. A third category of tyrosine kinases to be identified are those termed the growth factor receptors, which includes insulin, epidermal growth factor, and p185HER-2 receptors. All of these tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions.
Though the exact mechanisms of signal transduction have yet to be elucidated, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation. Therefore, inhibitors of these tyrosine kinases are useful for the prevention and chemotherapy of proliferative diseases dependent on these enzymes.
SUMMARY OF THE INVENTION
This invention is directed to benzylphosphonic compounds that are useful as tyrosine kinase inhibitors. The compounds of this invention have the formula ##STR1## and the pharmaceutically-acceptable cationic salts thereof, in which A can be a wide variety of lipophilic groups which are neither strongly basic nor strongly acidic. Typical groups for A are -phenyl, -benzoyl, ##STR2## n=0 or 1. "Amine" represents the radical NH-R, where NH.sub.2 --R is an esterified derivative of a naturally-occurring amino acid. Representative groups of NH-R are ##STR3##
The present invention is also directed to pharmaceutical compositions for the control of tyrosine kinase dependent diseases in mammals which comprise a compound of the formula (I) in a pharmaceutically-acceptable carrier; and to a method of controlling tyrosine kinase dependent diseases which comprises administering to a mammal suffering from tyrosine kinase dependent diseases a tyrosine kinase dependent disease controlling amount of a compound of the formula (I).
The expression "pharmaceutically-acceptable cationic salt" refers to nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,N'-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methylglucamine), benethamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
Other features and advantages will be apparent from the specification and claims.
DETAILED DESCRIPTION OF THE INVENTION
In general, the phosphonic acid compounds of this invention of formula I can be prepared by reacting the appropriate benzyl halide of formula II with a phosphite (the Arbusov reaction), followed by hydrolysis, as follows ##STR4## These reactions are carried out by standard methods, well-known in the art.
Reaction of the benzyl halide of formula II with the phosphite is usually carried out by heating with a phosphite at temperatures of about ambient (25.degree. C.) to about 150.degree. C., preferably about 60.degree. C. to about 90.degree. C., for about one to about 24 hours. Typically an excess of phosphite (e.g., 1.2 equivalents to about 10 equivalents) is used. The reaction may be run neat (typically with at least about a 5 equivalent excess of phosphite) or may be run in nonhydroxylic solvents such as nonpolar hydrocarbon solvents, ethereal solvents, etc. Specific examples include THF, DMF and toluene. Typically the reac
REFERENCES:
Okamoto, et al. Phosphorus Sulfur 35(1-2) 77-81 1988.
Okamoto, Y., et al., "Photochemical C-P Bond Cleavage of Some (Substituted Benzyl) phosphonic Acid Derivatives," J. Chem. Soc. Japan, No. 7:1255-1261 (1987).
Okamoto, Y., et al., "Photochemical C-P Bond Cleavage of Benzoylbenzylphosphonic Acids," Phosphourus and Sulfur, v. 35:77-81 (1988).
Petrakis, K. S., et al., "Palladium-Catalyzed Substitutions of Triflates Derived from Tyrosine-Containing Peptides and Simpler Hydroxyarenes Forming 4-(Diethoxyphosphinyl)phenylalanines and Diethyl Arylphosphonates," J. Am. Chem. Soc., 109:2831-2833 (1987).
Saperstein, R., et al., "Design of a Selective Insulin Receptor Tyrosine Kinase Inhibitor and Its Effect on Glucose Uptake and Metabolism in Intact Cells," Biocheminstry, 28:5694-5701 (1989).
Dow Robert L.
Goldstein Steven W.
Benson Gregg C.
Conrad, III Joseph M.
Dees Joee G.
Olson A. Dean
Pfizer Inc.
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