Method for lowering plasma lipid levels or blood pressure

Abstract
The invention relates to new gem-diphosphonates derivatives substituted by phenol groups of formula (I): ##STR1## as well as the process for their preparation and the pharmaceutical compositions containing them.
Description

This invention relates to a novel class of compounds, phenol substituted gen-diphosphonate derivatives as well as the process for preparing such compounds. It further relates to pharmaceutical compositions containing the above-mentioned compounds especially for the treatment of hyperlipidemia.
Many epidemiologic studies have shown that people with high levels of serum cholesterol are at high risk of developing coronary artery diseases. The convincing and definitive evidence that lowering serum cholesterol with the aid of hypocholesterolemic drugs reduces the risk of coronary heart diseases was provided by the Lipid Research Clinics Coronary Primary Prevention Trial reports (The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. Journal of the American Medical Association 251, p. 351-364, 1984. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. Journal of the American Medical Association 251, p. 365-374, 1984).
In addition, the most recent report from the Helsinki study showed that gemfibrozil treatment, which was associated with the modification of the serum lipoprotein levels and decreased plasma triglycerides, reduces the incidence of coronary heart disease in men with dyslipemia (The New England Journal of Medicine 317 (20), p. 1237-1245, 1987).
The phenol substituted gem-diphosphonates were tested and discovered to be potent hypolipidemic and lipid altering agents, in addition some were found to possess hypotensive activity. These gem-diphosphonates are therefore potentially useful agents for the treatment of dyslipemias and associated cardiovascular diseases.
H. Gross and coworkers have described the synthesis of (3,5-ditertiarybutyl-4-hydroxyphenyl)methylidene diphosphonic acid and its Me, Et and Pr esters in Journal f. prakt. Chemie 317(6), p. 890-896 (1975); ibid. 318(3), p. 403-408 (1976) and ibid. 320(2), p. 344-350 (1978). No potential application of these compounds was provided in the description.
W. Lehnert reported in Tetrahedron 30, p. 301-305 (1974) a method for the preparation of simple phenylethenylidene-diphosphonate and-carboxyphosphonate esters, without any information on their potential application.
The U.S. Pat. No. 4,696,920 (1987) of Symphar S.A. reports the preparation of tetraethyl and tetrabutyl 2-(3,5-ditertiarybutyl-4-hydroxy)benzyl-1,3-propylidenediphosphonate and their possible use in the treatment of cardiovascular diseases induced by or associated with the dysfunction of the low calcium channels.
The UK patent 2 043 072 (1979) of Symphar S.A. discloses the synthesis of unsubstituted phenyl- and phenoxy-alkylidene-1,1-diphosphonic acids and Me and Et esters and their application as antiatherosclerotic agents.
The present invention relates to compounds of formula (I): ##STR2## where: Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 identical or different are
OR where R is H, a straight, branched or cyclic alkyl group comprising from 1 to 8 carbon atoms,
OM where M is an alkali or alkaline earth metal ion or an ammonium group NR.sub.4 where R has the same meaning as defined above,
NR.sub.2 where R has the same meaning as defined above,
Z.sup.1, Z.sup.2 and Z.sup.3, Z.sup.4 may form an alkylidenedioxy ring comprising 2 to 8 carbon atoms.
X.sup.1, X.sup.2 identical or different, are H, a halogen atom, a straight, branched or cyclic alkyl or alkoxy group from 1 to 8 carbon atoms,
X.sup.3 is H, an alkyl group R.sup.1 from 1 to 4 carbon atoms, an acyl group C(O)R.sup.1, a carbamyl group C(O)NHR.sup.1 where R.sup.1 is described as above X.sup.3 O and one of the two other substituents X.sup.1 or X.sup.2 may form an alkylidenedioxy ring comprising from 1 to 4 carbon atoms,
A is --CH.dbd.CH--CH.sub.2 --, --(CH.sub.2).sub.n --, --O(CH.sub.2).sub.n --, --S--, SO.sub.2, --S(CH.sub.2).sub.n --, --SO.sub.2 (CH.sub.2).sub.n --, where n is an integer from 1 to 7, --(CH.dbd.CH).sub.k --(CH.sub.2).sub.d --CH.dbd. where k is zero or 1 and d is an integer from zero to 4,
B is H, an alkyl group from 1 to 4 carbon atoms,
t is zero or 1, with the proviso that t is zero only when A is (CH.dbd.CH).sub.k --(CH.sub.2).sub.d --CH.dbd. where k and d are as described above.
The compounds of formula (I) include the phenol substituted alkylidenediphosphonates (Ia) and the phenol substituted alkenylidenediphosphonates (Ib) ##STR3## where X.sup.1, X.sup.2, X.sup.3, A, B, k, d, Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 are as described above.
Compounds of structure (Ia) include, for example, those in which:
X.sup.1, X.sup.2 identical or different are alkyl groups from 1 to 8 carbon atoms,
X.sup.3 is hydrogen,
A is CH.dbd.CH--CH.sub.2, (CH.sub.2).sub.n, S, SO.sub.2, S--(CH.sub.2).sub.n, SO.sub.2 --(CH.sub.2).sub.n, where n is 1-7,
B is hydrogen or a C.sub.1 -C.sub.4 alkyl group,
Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 identical or different are OH, alkoxy groups of 1 to 8 carbon atoms or one or both of the pairs Z.sup.1, Z.sup.2 and Z.sup.3, Z.sup.4 are an alkylidenedioxy group of 2 to 8 carbon atoms.
Compounds of structure (Ib) include, for example, those in which
X.sup.1, X.sup.2 identical or different are alkyl groups from 1 to 8 carbon atoms,
X.sup.3 is hydrogen,
k is zero or 1 and d is zero to 4,
Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 identical or different are OH, alkoxy groups of 1 to 8 carbon atoms or one or both of the pairs Z.sup.1, Z.sup.2 and Z.sup.3, Z.sup.4 are an alkylidenedioxy group of 2 to 8 carbon atoms.
PROCESS FOR PREPARING COMPOUNDS OF FORMULA (I)
The present invention also relates to a process for preparing gem-diphosphonates of formula (Ia) and (Ib).
The experimental procedure for preparing (Ia) consists in reacting the diphosphonate compound III with a base such as sodium hydride, sodium metal, sodium alkoxide, n-butyl lithium or lithium diisopropylamide. The starting product II is then reacted with the anion of compound III thus formed in situ to give the substituted diphosphonate (Ia). The reaction takes place in solvents such as hexane, heptane, benzene, toluene, tetrahydrofuran, dioxane, dimethoxyethane, methyl tertiobutyl ether or N, N-dimethylformamide. The solvents can be utilized pure or as a mixture, depending on the solvent polarity desired. The temperature range of the reaction is between -78.degree. C. and the boiling point of the solvent or solvent mixture. The reaction time varies between several hours and several days. In the case where A is a sulfur atom, the appropriate starting compound II is the bis (substituted phenol) disulfide and the preferred base is n-butyl lithium.
The procedure for preparing (Ib) consists in condensing the appropriate aldehyde IV with the diphosphonate compound V using titanium tetrachloride and a tertiary amine such as methyl morpholine or pyridine as catalysts. The reaction is carried out in an ether solvent such as tetrahydrofuran, dioxane or dimethoxyethane. The polarity of the reaction medium can be conveniently modified by adding a non-polar solvent such as tetrachloromethane. The temperature of the reaction varies between -15.degree. C. and 40.degree. C., preferably between 0.degree. C. and 30.degree. C.
The obtained alkenylidene-diphosphonates (Ib) can be hydrogenated to the corresponding alkylidene-diphosphonates (Ia) where B=H. In the particular case where structure (Ib) contains two double bonds, i.e. when k=1, the reduction conditions can be made to form either of the following two compounds (Ia): the partially saturated compound where A=(CH.dbd.CH).sub.k --(CH.sub.2).sub.d --CH.sub.2, B=H, or the completely saturated compound where A=(CH.sub.2 --CH.sub.2).sub.k --(CH.sub.2).sub.d --CH.sub.2, B=H.
The partially saturated compound (Ia) where A=(CH.dbd.CH).sub.k --(CH.sub.2).sub.d --CH.sub.2, B=H, can be made predominantly when (Ib), where k=1, is reduced with a complex hydride reagent such as sodium borohydride or lithium borohydride in a polar solvent which can be methanol, ethanol at a temperature between -15.degree. and room temperature.
The completely saturated compound (Ia) where A=(CH.sub.2 CH.sub.2).sub.k --(CH.sub.2).sub.d --CH.sub.2, B=H, can be obtained from (Ib), where k=1, by reduction with an excess of complex hydride reagent such as sodium borohydride or lithium borohydride in methanol or ethanol as solvent at a temperature between room and reflux temperature. Another convenient reduction method is the catalytic hydrogenation using palladium or platinum adsorbed on active charcoal as catalyst. Suitable solvents include methanol, ethanol, dimethoxyethane, dioxane, tetrahydrofuran and acetic acid. The reduction is performed at room temperature and at a pressure between 1 and 4 atm.
Compounds (I) obtained through one of the procedures described in page 8 can be derivatized into other products with different ester groups. One such method involves the hydrolysis of the tetraethyl ester compounds (I), Z.sup.1 --Z.sup.4 .dbd.OEt, with hydrochloric acid or bromotrimethylsilane/water to yield the corresponding diphosphonic acids (I), Z.sup.1 --Z.sup.4 .dbd.OH. The latter compounds are alkylated by using trialkyl orthoformates to form the corresponding tetraalkyl esters. An alternative method consists in reacting the tetraethyl ester derivative with bromotrimethylsilane/phosphorus pentachloride to form the diphosphnoyl tetrachloride. The esterification of this intermediate with various alcohols or diols yields new derivatives (I) where the pairs of substituents Z.sup.1, Z.sup.2 and Z.sup.3, Z.sup.4 may be individual alkoxy groups or may form alkylidenedioxy groups.
The above described synthetic procedures are described immediately hereafter. ##STR4##
When A is S--(CH.sub.2).sub.n or O--(CH.sub.2).sub.n, (Ia) can also be prepared by reacting bromalkylidenediphosphonate VIII with respectively the thiohydroquinone VI or hydroquinone derivative VII in presence of a base. ##STR5##
When A is S--(CH.sub.2).sub.n where n.gtoreq.3, one additional method for preparing (Ia) involves reacting VI with an alkenylidenediphosphonate IX in presence of a radical initiating agent such as benzoyl peroxide or hydrogen peroxide. ##STR6##
The sulfide group is converted to the higher oxidation states, namely the sulfone groups, by using an oxidative agent which may be a peracid such as m-chloroperbenzoic acid or a peroxide salt such as potassium permanganate or potassium hydrogen persulfate. ##STR7##
Compounds (I) where X.sup.3 is different from H can be prepared by using the corresponding starting compound II where X.sup.3 .noteq.H. One alternative method involves derivatizing the phenolic --OH group in compounds (I) by standard synthetic procedures: alkylation, by reacting the phenoxide anion with alkylating reagents such as alkyl halide or dialkyl sulfate, esterification by using acylating reagents such as acid anhydrides or acyl halides to form the corresponding esters or by using isocyanates to form the corresponding carbamates.
The starting compounds V which are not commercially available are prepared by one of the two following methods.
Arbuzov reaction between an alkyl phosphite and a halogenomethylphosphate ##STR8## Transesterification of the methylenediphosphonate ethyl ester ##STR9##
These two methods provide new starting compounds V where the substituents Z.sup.1, Z.sup.2, Z.sup.3, Z.sup.4 may be individual alkoxy groups or where the pairs of substituents Z.sup.1, Z.sup.2 and/or Z.sup.3, Z.sup.4 may form alkylidenedioxy rings.
The structures of compounds of formula (I) are determined by elemental analysis, infrared (IR), mass (MS) and nuclear magnetic resonance (NMR) spectroscopies. The purity of the compounds is verified by thin layer chromatography (Silicagel, CH.sub.2 Cl.sub.2 /MeOH or CHCl.sub.3 /MeOH eluent mixtures), gas liquid chromatography (Methyl silicone column) or high performance liquid chromatography (Octadecylsilane C.sub.18 reversed phase column).
The abbreviations used in this patent application are as follows:
In Tables 1 and 2, n- is normal, i- is iso-, sec is secondary-, t is tertiary. In the NMR spectra, s is singlet, d is doublet, t is triplet, m is multiplet. The temperatures are measured in degree Celsius and the melting points are uncorrected. The boiling points refer to values obtained by short path distillation carried out in a ball tube type distillation apparatus (Kugelrohr).
The present invention will be further described by the Examples 1 to 23 which are typical of the synthetic procedures used.





EXAMPLE 1 (COMPOUND 7)
Tetrabutyl 2-(3,5-ditertiary-4-hydroxyphenyl)-ethylidene-1,1-diphosphonate ##STR10##
A solution of 3,5-ditertiary-4-hydroxybenzyl bromide (2.48 g, 8.3 mmol) in 30 ml dioxane was added to a solution of 12.5 mmol of sodium tetrabutyl methylenediphosphonate prepared by reacting an equimolar amount of NaH and tetrabutyl methylenediphosphate in 30 ml tetrahydrofuran. The reaction mixture was refluxed for 16 h then was partitioned between H.sub.2 O and CHCl.sub.3. The dried organic phase (MgSO.sub.4) was evaporated and the residue was purified by column chromatography (SiO.sub.2, CHCl.sub.3 then 95/5 CHCl.sub.3 /MeOH) to afford 2.9 g (4.6 mmol, 56%) of tetrabutyl 2-(3,5-ditertiary-4-hydroxyphenyl)-ethylidene-1,1-diphosphonate.
IR (film): 2980 cm.sup.-1 : aliphatic C--H 1440: t--C.sub.4 H.sub.9, 1240: P.dbd.O, 1020-970: P--O--C.
NMR (CDCl.sub.3): .delta.=7.05 (s, 2H): aromatic H, 5.08 (s, 1H) OH, 4.1-3.95 (m, 8H): P--O--CH.sub.2 --C.sub.3 H.sub.7, 3.18 (t.times.d, J=7 and 16 Hz, 2H): Ph--CH.sub.2 --, 2.66 (t.times.t, J=7 and 24 Hz, 1H: Ph--CH.sub.2 CH, 1.60 (sextet, J=7 Hz, 8H): P--O--CH.sub.2 CH.sub.2 --C.sub.2 H.sub.5, 1.44 (s, 18H): t--C.sub.4 H.sub.9, 138 (multiplet, J=7 Hz, 8H): P--O--C.sub.2 H.sub.4 --CH.sub.2 --CH.sub.3, 0.90 (2.times.t, J=7 Hz, 12H): P--O--C.sub.3 H.sub.6 --CH.sub.3.
EXAMPLE 2 (Compound 5)
Tetraethyl 3,5-ditertiary-4-hydroxyphenylthio-methylenediphosphonate ##STR11##
To a solution of tetraethyl methylenediphosphonate (2.43 g, 8.43 mmol) in 15 ml dry tetrahydrofuran were added 5.3 ml (8.43 mmol) of 1.6M n-butyllithium in hexane at -78.degree. under nitrogen. To the above solution were then added 15 ml of a tetrahydrofuran solution of 4.0 (8.43 mmol) of bis(3,5-ditertiard-4-hydroxyphenyl)disulfide, prepared according to T. Fujisawa et al., Synthesis 1972, pp. 624-625. The mixture was maintained at -78.degree. C. for 1 h and then stirred at 25.degree. C. for 3 days. Hydrolysis was performed with 20 ml saturated NH.sub.4 Cl solution and the mixture was extracted with 3.times.40 ml diethyl ether. The organic phase was dried over MgSO.sub.4, evaporated and the residue was purified by column chromatography (SiO.sub.2, 95/5 CH.sub.2 Cl.sub.2 /MeOH). It was obtained 2.2g (4.2 mmol) of a yellow oil which slowly crystallized; yield=49%.
mp=78-80.degree. C.
Elemental analysis: C.sub.23 H.sub.42 H.sub.42 O.sub.7 P.sub.2 S;
% calc. C, 52.66; H, 8.07; P, 11.88; S, 6.11.
% found C, 52.13; H, 7.77; P, 11.65; S, 6.62.
IR (film): 3600+3450 cm.sup.-1 : OH 1430: t-C.sub.4 H.sub.9, 1250: P.dbd.O, 1040: P--O--C. NMR (CDCl.sub.3): .delta.=7.5 (s, 2H): aromatic H, 5.4 (s, 1H): OH, 4.35-4.2 (m, 8H): P--O--CH.sub.2 CH.sub.3, 3.55 (t, J=21 Hz, 1H): --CH--PO.sub.3 Et.sub.2, 1.45 (s, 18H): t-C.sub.4 H.sub.9, 1.35 (t, J-7 Hz, 12H): P--O--CH.sub.2 --CH.sub.3.
MS: 524 (M.sup.+)
EXAMPLE 3 (COMPOUND 4)
Tetraethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonate ##STR12##
Tetraethyl methylenediphosphonate (21.2 g, 73.5 mmol) was added at room temperature to a 80% dispersion of sodium hydride in mineral oil (2.2 g, 73.5 mmol) suspended in 70 ml dry benzene. To this solution of sodium tetraethyl methylenediphosphonate was then added a 30 ml toluene solution of 20 g (66.8 mmol) of 3,5-ditertiarybutyl-4-hydroxybenzylbromide prepared according to H. Gross, H. Seibt and I. Keitel, Journel fur prakt. Chemie 317 (6), p. 890-896 (1975). The resulting mixture was refluxed for 16 hours. The cooled toluene phase was extracted with H.sub.2 O, dried over MgSO.sub.4 and evaporated to dryness. The residue was purified by colunm chromatography (SiO.sub.2, pure CHCl.sub.3 followed by a 95/5 CHCl.sub.3 /MeOH solution) to give 21.3 g (63% yield) of tetraethyl2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonate.
mp=62.degree.-63.degree. C.
Elemental analysis: C.sub.24 H.sub.44 O.sub.7 P.sub.2, % calc. C, 56.90; H, 8.76; P 12.23. % found C, 56.76; H, 8.53; P, 12.15.
IR (KBr): 3400 cm.sup.-1 : O--H, 2850: aliphatic C--H, 1440: t-butyl, 1240: P.dbd.O, 1040: P--O--C.
NMR (CDCl.sub.3): .delta.=7.1 (s, 2H): aromatic H, 5.1 (s, 1H): OH, 4.15-4.05 (m, 8H): P--O--CH.sub.2 CH.sub.3, 3.18 (t.times.d, J=6 and 17 Hz, 2H): Ph--CH.sub.2, 2.65 (t.times.t, J=6 and 24 Hz, 1H): Ph--CH.sub.2 --CH, 1.45 (s, 18H): tC.sub.4 H.sub.9, 1.26 (two overlapping t, J=7 Hz, 12H): P--O--CH.sub.2 --CH.sub.3.
EXAMPLE 4 (COMPOUND 13)
Tetraethyl 2-(3,4-methylenedioxy-6-chlorophenyl)-ethylidene-1,1-diphosphonate ##STR13##
To a solution of sodium tetraethyl methylenediphosphonate (22 mmol) in 15 ml dry dimethoxyethane were added 4.1 g (20 mmol) of 6-chloropiperonyl chloride. After 16 h at reflux the reaction mixture was partitioned between Et.sub.2 O (3.times.20 ml) and H.sub.2 O (20 ml) and the organic phase was dried over MgSO.sub.4. Short path distillation (kugelrohr) gave 3.1 g (8.5 mmol, 43%) of the title compound.
bp=200.degree. C./0.05 mmHg.
IR (film) 2950 cm.sup.-1 : aliphatic C--H, 1240: P.dbd.O, 1030: P--O--C+OCH.sub.2 O.
Elemental analysis: C.sub.17 H.sub.27 ClO.sub.8 P.sub.2 ; % calc. C, 44.70; H, 5.96; P, 13.56; Cl, 7.56. % found C, 44.51; H, 6.21; P, 13.41; Cl, 7.65.
NMR (CDCl.sub.3): .delta.=6.76(s, 1H): aromatic H, 6.70(s, 1H): aromatic H, 5.84(s, 2H): O--CH.sub.2 --O, 4.10-3.96(m,8H): P--O--CH.sub.2 CH.sub.3, 3.10-3.20(m, 2H): Ph--CH.sub.2, 2.80(t.times.t, J=7 and 24 Hz, 1H): Ph--CH.sub.2 CH, 1.12 (two overlapping t, J=7 Hz, 12H): P--O--CH.sub.2 CH.sub.3.
EXAMPLE 5 (COMPOUND 30)
Tetraethyl 2-(3-tertiarybutyl-4-hydroxy-5-methylphenyl)-ethenylidene-1,1-diphosphonate ##STR14##
Under nitrogen, 300 ml of dry tetrahydrofuran were placed in a 500 ml reactor and were cooled to 0.degree.. Titanium tetrachloride (27.5 g, 145 mmol) was added dropwise followed by 10 g (52 mmol) of 3-tertiobutyl-4-hydroxy-5-methylbenzaldehyde synthesized according to G. A. Nikiforov et al, Izv. Akad. Nauk SSSR, Otd. Khim. Nauk 1962, p. 1836-8; Chem. Abst. 58, 7856f (1963). Tetraethyl methylenediphosphonate (21 g, 72 mmol) was added followed by pyridine (22.9 g, 290 mmol). The mixture was stirred for 3 h at room temperature and concentrated under vacuum. The residue was partitioned between Et.sub.2 O and H.sub.2 O. The ether phase was washed with NaHCO.sub.3 solution to pH 7, dried and evaporated to dryness. An amount of 18.5 g (40 mmol, 77% yield) was obtained of the title compound, pure by GLC.
IR (film): 3400 cm.sup.-1 : OH, 2950: aliphatic C--H, 1240: P.dbd.O, 1060: P--O--C.
NMR (CDCl.sub.3): .delta.=8.2 (d.times.d, J=30 and 50 Hz, 1H): Ph--CH.dbd.CP.sub.2, 7.7-7.6 (m, 2H): aromatic H, 4.25-4.05 (m, 8H): P--O--CH.sub.2 CH.sub.3, 2.25 (s, 3H): CH.sub.3, 1.4 (s, 9H): t--C.sub.4 H.sub.9, 1.35 and 1.2(2.times.t, 12H): P--O--CH.sub.2 --CH.sub.3.
EXAMPLE 6 (COMPOUND 33)
Tetraethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethenylidene-1,1-diphosphonate ##STR15##
An amount of 700 ml dry tetrahydrofuran was placed in a 1l reactor under nitrogen atmosphere. Titanium tetrachloride (96.5 g, 0.51 mol) was added to the THF solution cooled to 0.degree., followed by 40.0 g (0.17 mol) 3,5-ditertiarybutyl-4-hydroxybenzaldehyde. Tetraethyl methylenediphosphonate (69.1 g, 0.24 mol) was added dropwise, followed by methylmorpholine (97.6 g, 0.97 mol) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was then partitioned between H.sub.2 O and diethyl ether. The ether phase was washed until neutral pH, dried and evaporated. The residue was recrystallized in acetone and the mother liquor purified by column chromatography (SiO.sub.2 pure CHCl.sub.3 followed by 95/5 CHCl.sub.3 /MeOH). The combined fractions gave 53 g (0.11 mol, 62% yield) of tetraethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethenylidene-1,1-diphosphonate.
mp=120.degree.-121.degree. C.
Elemental analysis: C.sub.24 H.sub.42 O.sub.7 P.sub.2 ; % calc. C, 57.14; H, 8.39; P, 12.28. % found C, 56.89; H, 8.23; P, 12.05.
IR (KBr): 3200 cm.sup.-1 : OH, 2850: aliphatic C--H, 1570: C.dbd.C 1440: t-butyl, 1240: P.dbd.O, 1060: P--O--C.
NMR (CDCl.sub.3): .delta.=8.25 (d.times.d, J=30 and 48 Hz, 1H): Ph--CH.dbd.C--P.sub.2, 7.7 (m, 2H): aromatic H, 5.65 (s, 1H): OH, 4.2-4.0 (2.times.m, 8H): P--O--CH.sub.2 --CH.sub.3, 1.5 and 1.45 (2.times.s, 18H): t--C.sub.4 H.sub.9, 1.4 and 1.2 (2.times.t, 12H): P--O--CH.sub.2 CH.sub.3.
EXAMPLE 7 (COMPOUND 38)
Tetraethyl 2(3,4-methylenedioxyphenyl)-ethenylidene-1,1-diphosphonate ##STR16##
Under nitrogen, TiCl.sub.4 (11 ml, 100 mmol) was added dropwise to a 200 ml solution of dry THF cooled to 0.degree. C. Sequentially were added piperonal (7.5 g, 50 mmol) dissolved in 30 ml THF, tetraethyl methylenediphosphonate (14.4 g, 50 mmol) and N-methylmorpholine (20.2 g, 200 mmol). The mixture was stirred at room temperature for 90 min, H.sub.2 O (50 ml) was added and the resulting mixture was extracted by Et.sub.2 O (3.times.100 ml). The residue of the organic phase was purified by column chromatography (SiO.sub.2, 95/5 CHCl.sub.3 /MeOH) to give 13.7 g (32.6 mmol, 66%) of the title compound.
IR (film): 2980, 1560 (C.dbd.C), 1250 (P.dbd.), 1030 (P--O--C).
Elemental analysis: C.sub.17 H.sub.26 O.sub.8 P.sub.2 ; % calc. C, 48.58; H, 6.24; P, 14.74. % found C, 48.20; H, 6.01; P, 14.21.
NMR (CDCl.sub.3): .delta.=8.26-8.04 (d.times.d, J=48 and 30 Hz, 1H): Ph--CH.dbd.C, 7.52 (S, 1H): aromatic H, 7.28 (d, 1H): aromatic H, 6.80 (d, 1H): aromatic H, 5.98 (S, 2H): O--CH.sub.2 --O, 4.15 and 1.05 (two m, 8H): P--O--CH.sub.2 CH.sub.3, 1.30 and 1.16 (two t, 12H): P--O--CH.sub.2 CH.sub.3.
EXAMPLE 8 (COMPOUND 1)
Tetraethyl 2-(3-tertiarybutyl-4-hydroxy-5-methylphenyl)-ethylidene-1,1-diphosphonate ##STR17##
An amount of 11.4 g (24.6 mmol) of tetraethyl 2-(3-tertiarybutyl-4-hydroxy-5-methylphenyl)-ethenylidene-1,1-diphosphonate was added to a solution of 4.65 g (123 mmol) NaBH.sub.4 in EtOH and the mixture was refluxed for 90 min. The ethanol solution was evaporated and the residue was partitioned between 2.5N HCl and Et.sub.2 O. Evaporation of the dried organic phase gave an oil which was purified by short-path distillation. 9.9 g (87% yield) of tetraethyl 2-(3-tertiarybutyl-4-hydroxy-5-methylphenyl)-ethylidene-1,1-diphosphonate were obtained.
bp=190.degree. C. (0.05 mmHg).
Elemental analysis: C.sub.21 H.sub.38 O.sub.7 P.sub.2 ; % calc. C, 54.30; H, 8.25; P, 13.34. % found C, 54.04; H, 8.15; P, 12.94.
IR (film): 3400 cm.sup.-1 : OH, 2850: aliphatic C--H, 1240: P.dbd.O, 1060: P--O--C.
NMR (CDCl.sub.3): .delta.=7.0-6.9 (m, 2H): aromatic H, 4.2-4.05 (m, 8H): P--O--CH.sub.2 --CH.sub.3, 3.14 (d.times.t, J=6 and 18 Hz, 2H): Ph--CH.sub.2, 2.6 (t.times.t, J=6 and 24 Hz, 1H): Ph--CH.sub.2 --CH, 2.2 (s, 3H): CH.sub.3, 1.4 (s, 9H): t--C.sub.4 H.sub.9, 1.25 (2.times.t, 12H): P--O--CH.sub.2 --CH.sub.3.
EXAMPLE 9 (COMPOUND 4)
Tetraethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonate ##STR18##
A 80 ml ethanol solution of tetraethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl-ethenylidene-1,1-diphosphonate (25.3 g, 50 mmol) (compound 33) was added under nitrogen to a suspension of lithium borohydride (3.3 g, 150 mmol) in 250 ml ethanol and the mixture was refluxed for 1 h. The solvent was evaporated and the residue was taken up in diethyl ether. The ether phase was washed with a 10% HCl solution, H.sub.2 O until pH 6 and then dried over MgSO.sub.4. Evaporation of the ether solution gave 24 g (47 mmol, 95% yield) of tetraethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethylidene-1,1 -diphosphonate.
The reduction of compound 33 can also be carried out by catalytic hydrogenation.
A mixture of compound 33 (1 g, 2 mmol) and 20 mg of 10% Palladium on active charcoal (10% Pd/C) in 50 ml acetic acid was hydrogenated at room temperature and 1.5 atm pressure for 16 h. Filtration of the catalyst and evaporation of the solvent gave 1.0 g (2 mmol, 100%) of the title compound.
Platinum on active charcoal (10% Pt/C) can also be used with equally good results. A mixture of compound 33 (1 g, 2 mmol) and 20 mg 10% Pt/C in 50 ml CH.sub.3 COOH was hydrogenated at room temperature and 1.2 atm for 16 h and gave after work up 1 g of compound 4 (2 mmol), 100%).
The compound prepared by these reduction procedures has physical and spectroscopic data identical to those of the product described in Example 3.
EXAMPLE 10 (COMPOUND 8)
2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonic acid ##STR19##
Under anhydrous conditions, trimethylbromosilane (5 ml, 38.6 mmol) was added dropwise to 10 ml of carbon tetrachloride solution of tetraethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonate (1.95 g, 3.86 mmol). The mixture was stirred at room temperature for 30 h. The excess of BrSiMe.sub.3 was removed by distillation and the residue was treated with 20 ml H.sub.2 O for 2 h. Evaporation of the aqueous solution gave 1.43 g (3.6 mol, 94%) of the diphosphonic acid.
mp=177.degree.-178.degree. C.
IR (KBr): 360 cm.sup.-1 : OH 3000-2500: P--O--H, 1430: t--C.sub.4 H.sub.9, 1200: P.dbd.O.
Compound 8 can also be obtained by hydrolysis with hydrochloric acid.
A mixture of compound 4 (2.5 g, 50 mmol) in 10 ml of 37% HCl was heated to 115.degree. for 16 h. The evaporation to dryness of HCl provided 1.9 g (4.8 mmol, 96%) of 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonic acid.
EXAMPLE 11 (COMPOUND 10)
Tetramethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonate ##STR20##
A mixture of 3.5 g (8.9 mmol) 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonic acid and 10 g (94 mmol) trimethylorthoformate was refluxed for one hour. The methyl formate and methanol formed were distilled off. Fresh trimethyl orthoformate (10 g, 94 mmol) was added and the mixture was refluxed for one hour. Removal of excess reagent and short path distillation (200.degree. C., 0.05 mmHg) gave 2.5 g (65%) of tetramethyl 2-(3,5-ditertiobutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonate.
mp=77.degree.-78.degree. C.
IR(KBr): 3400 cm.sup.-1 : O--H, 2850: aliphatic C--H, 1430: t-butyl, 1245: P.dbd.O, 1185: P--O--Me 1030: P--O--C.
NMR (CDCl.sub.3): .delta.=7.25 and 7.05 (m, 2H): aromatic H, 5.0 (s, 1H): OH, 3.7--3.65 (two d, J=11 Hz, 12H): P--O--CH.sub.3, 3.1 (t.times.d, J=6 and 17 Hz, 2H): Ph--CH.sub.2, 2.6 (t.times.t, J=6 and 24 Hz, 1H): Ph--CH.sub.2 --CH, 1.35 (s, 18H): t-C.sub.4 H.sub.9.
EXAMPLE 12 (COMPOUND 15)
Tetraethyl 1-(3,5-ditertiarybutyl-4-methoxyphenyl)propylidene-2,2-diphosphonate ##STR21##
Tetraethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonate (500 mg, 1 mmol) was added to a suspension of 80% NaH (40 mg, 1.3 mmol) in 20 ml of dry THF. Methyl iodide (1.3 ml, 6 mmol) was added and the reaction mixture was refluxed for 16 h. After Et.sub.2 O/H.sub.2 O extraction, the organic phase was dried and evaporated. Column chromatography (SiO.sub.2 , 95/5 CHCl.sub.3 /MeOH) gave 440 mg (0.84 mmol, 84%) of the title compound.
IR: 2980 cm.sup.-1 : aliphatic C--H, 1240: P.dbd.O, 1030: P--O--C.
MS: 534 (M.sup.+), 397 (100%, M--PO.sub.3 Et.sub.2).sup.+, 233.
EXAMPLE 13 (COMPOUND 14)
Tetraethyl 2-(3,5-ditertiarybutyl-4-acetoxyphenyl)-ethenylidene-1,1-diphosphonate ##STR22##
A mixture of tetraethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethenylidene-1,1-diphosphonate (3 g, 6 mmol) and a catalytic amount (50 mg) H.sub.2 SO.sub.4 in 3 g of acetic anhydride was warmed to 80.degree. C. for 3 h. The reaction mixture was poured on ice and extracted in Et.sub.2 O. The organic phase was washed with H.sub.2 O and dried over MgSO.sub.4 and evaporated to dryness. The residue was purified by column chromatography (SiO.sub.2 , 95/5 CHCl.sub.3 /MeOH) to give 2.32 g (4.2 mmol, 71% yield) of the title compound.
IR: 2840 cm.sup.1 : aliphatic C--H, 1760: C.dbd.O, 1560: C.dbd.C, 1240: P.dbd.O, 1030: P--O--C.
EXAMPLE 14 (COMPOUND 17)
Tetraethyl 4-(3,5-ditertiarybutyl-4-hydroxyphenylthio)-butylidene-1,1-diphosphonate ##STR23##
A mixture of 1.0 g (3.04 mmol) of tetraethyl 3-butenylidene-1,1-diphosphonate prepared by reaction of tetraethyl methylene diphosphonate and allyl bromide, 0.8 g (3.36 mmol) of 3,5-ditertiarybutyl-4-hydroxyphenylmercaptan and 0.022 g (0.09 mmol) of dibenzylperoxide was refluxed in benzene overnight. After evaporation of the solvent, the crude product was column chromatographied and 0.44 g (25% yield) of tetraethyl 4-(3,5-ditertiarybutyl-4-hydroxyphenylthio)-butylidene-1,1-diphosphonate was isolated.
IR (film): 3400 cm.sup.-1 : O--H, 2850: aliphatic C--H, 1430: t-butyl, 1240: P.dbd.O, 1020: P--O--C.
MS: 566 (M.sup.+), 429 (M--PO.sub.3 Et.sub.2).sup.+.
EXAMPLE 15 (COMPOUND 19)
Diethyl 1-bis(dimethylamino)phosphinyl-2-(3,5-ditertiarybutyl-4-hydroxyphenyl)ethylphosphonate ##STR24##
Diethyl bis(dimethylamino)phosphinyl methylphosphonate was prepared by reacting diethyl methylphosphonate and bis(dimethylamino) phosphorochlorinate using lithium diisopropylamide in THF, according to P. Savignac et al, Tetrahedron Letters 26 (37), p. 4435-4438 (1985).
Diethyl bis(dimethylamino)phosphinyl methylphosphonate (1.4 g, 5 mmol) was added at room temperature to a suspension of 80% NaH (0.15 g, 5 mmol) in 20 ml dry tetrahydrofuran. A solution of 3,5-ditertiarybutyl-4-hydroxybenzylbromide (1.5 g, 5 mmol) in 20 ml dioxane was added and the mixture was refluxed overnight. After evaporation of the solvents, the residue was partitioned between H.sub.2 O and CHCl.sub.3. The residue of the organic phase was purified by column chromatography (SiO.sub.2, 95/5 CHCl.sub.3 /MeOH) to give 490 mg (20% yield) of the title compound.
IR (film): 3400 cm.sup.-1 : OH, 2860: aliphatic C--H, 1440: t-C.sub.4 H.sub.9, 1240+1220: P.dbd.O, 1030: P--O--C.
MS: (m/e).sup.+ : 504 (M.sup.+); 369 (100%, M.sup.+ -PO(NMe.sub.2).sub.2); 135 (PO(NMe.sub.2).sub.2).sup.+.
NMR (CDCl.sub.3): .delta.=7.08 (s, 2H): aromatic H, 5.08 (s, 1H): OH, 4.1-3.9 (m, 4H): P--O--CH.sub.2 CH.sub.3, 3.25-3.1 (large m, 2H): Ph--CH.sub.2 --CH, 2.9-2.7 (large m, 1H): Ph--CH.sub.2 --CH, 2.5 and 2.55 (two d, J=9 Hz, 12H): N--CH.sub.3, 1.38 (s, 18H): t-C.sub.4 H.sub.9, 1.15 (two t, J=7 Hz, 6H): P--O--CH.sub.2 CH.sub.3. EXAMPLE 16 (COMPOUND 16)
Tetraethyl 3,5-ditertiarybutyl-4-hydroxyphenylsulfonylmethylenediphosphonate ##STR25##
A solution of 800 mg (1.26 mmol) of 49.5% KHSO.sub.5 (Potassium hydrogen persulfate, "oxone") in 0.8 ml H.sub.2 O was added to a solution of 400 mg of tetraethyl 3,5-ditertiarybutyl-4-hydroxyphenylthio-methylene diphosphonate (compound 5) (0.84 mmol) in 5 ml CH.sub.3 OH while stirring in an ice bath. The resulting slurry is stirred overnight and the mixture is concentrated to remove MeOH. The residue is partitioned between H.sub.2 O and CH.sub.2 Cl.sub.2. The organic phase is washed with H.sub.2 O until neutral pH, concentrated and the residue is purified by column chromatography (CHCl.sub.3 /MeOH). An amount of 200 mg (0.36 mmol, 29%) of tetraethyl 3,5-ditertiarybutyl-4-hydroxyphenylsulfonyl-methylenediphosphonate was obtained.
mp=118.degree.-120.degree. C.
MS: (m/e): 556 (M.sup.+), 492 ((M-SO.sub.2).sup.+, 100%), 355 (M-PO.sub.3 Et.sub.2).sup.+.
A mixture of compound 5 (400 mg, 0.76 mmol) and 85% m-chloroperbenzoic acid (0.5 g, 2.5 mmol) in 5 ml CH.sub.2 Cl.sub.2 was stirred at room temperature for 16 h. The organic solution was extracted with saturated NaHSO.sub.3, saturated NaHCO.sub.3 and dried over MgSO.sub.4. Column chromatography purification (CHCl.sub.3 /MeOH) gave 160 mg of compound 16 (0.28 mmol, 38%). EXAMPLE 17 (COMPOUND 42)
Dibutyl diethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethenylidene-1,1-diphosphonate ##STR26##
Dibutyl diethyl methylenediphosphonate was prepared in 43% yield by reacting sodium dibutyl phosphite with diethyl chloromethylphosphonate, bp=140.degree. (0.05 mmHg), (Kugelrohr).
Dibutyl diethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethenylidene-1,1-diphosphonate was synthesized by reacting TiCl.sub.4 (4.94 g, 26 mmol), 3,5-ditertiarybutyl-4-hydroxybenzaldehyde (3 g, 13 mmol), dibutyl diethyl methylenediphosphonate (4.4 g, 13 mmol) and N-methylmorpholine (5.25 g, 52 mmol) in 20 ml THF at room temperature. Column chromatography (95/5 CHCl.sub.3 /MeOH) afforded 2.6 g (4.6 mmol, 36%) of the title compound.
IR (film): 2980 cm.sup.-1 : aliphatic C--H, 1560: C.dbd.C, 1430: t-C.sub.4 H.sub.9, 1240: P.dbd.O, 1020-970: P--O--C.
MS: (m/e): 560 (M.sup.+), 423 (M-PO.sub.3 Et.sub.2).sup.+, 367 (M-PO.sub.3 Bu.sub.2).sup.+, 311.
EXAMPLE 18 (COMPOUND 21)
Tetraethyl 1-(3,5-ditertiarybutyl-4-hydroxyphenyl)-butylidene-2,2-diphosphonate ##STR27##
Tetraethyl propylidene-1,1-diphosphonate was prepared in 65% yield by reacting tetraethyl methylenediphosphonate with ethyl iodide in presence of NaH in tetrahydrofuran.
Tetraethyl propylidene-1,1-diphosphonate (1.5 g, 4.75 mmol) was added to a suspension of 80% NaH (0.143 g, 4.75 mmol) in dry THF (10 ml) and the mixture was stirred until the NaH disappeared. 3,5-ditertiarybutyl-4-hydroxybenzylbromide (1.42 g, 4,75 mmol) in 5 ml THF was added and the mixture was refluxed for 4 h. After work up, column chromatography (SiO.sub.2, 95/5 CHCl.sub.3 /MeOH) gave 0.9 g (1.7 mmol, 36%) of the title compound. mp=107.degree.-110.degree. C.
IR (film): 3400 cm.sup.-1 : OH 2850: aliphatic C--H 1440: t-butyl, 1240: P.dbd.O 1040: P--O--C.
NMR (CDCl.sub.3): .delta.=7.15 (m, 2H): aromatic H, 5.1 (s, 1H): OH, 4.2-4.04 (m, 8H): O--CH.sub.2 --CH.sub.3, 3.2 (two d, J=12 and 16 Hz, 2H): Ph--CH.sub.2 --CP.sub.2, 2.1-1.9 (m, 2H): --C(P.sub.2)--CH.sub.2 --CH.sub.3, 1.45 (s, 18H): tC.sub.4 H.sub.9, 1.3-1.15 (several t, J=7 Hz, 15H): --C(P.sub.2)--CH.sub.2 --CH.sub.3 +O--CH.sub.2 CH.sub.3. EXAMPLE 19 (COMPOUND 20)
Tetraethyl 7-(3,5-ditertiarybutyl-4-hydroxyphenylthio)-heptylidene-1,1-diphosphonate ##STR28##
Tetraethyl 7-bromoheptylidene-1,1-diphophonate was prepared by reaction of sodium tetraethyl methylenediphosphonate with 1,6-dibromohexane.
A 20 ml tetrahydrofuran solution containing 4.2 mmol of the sodium salt of 3,5-ditertiarybutyl-4-hydroxyphenyl mercaptan was added to 20 ml of a tetrahydrofuran solution containing tetraethyl 7-bromoheptylidene-1,1-diphosphonate (1,89 g, 4.2 mmol). The reaction mixture was stirred at room temperature overnight. After hydrolysis and extration into Et.sub.2 O, the crude compound was purified by column chromatography (SiO.sub.2, 95/5 CHCl.sub.3 /MeOH) to yield 1.6 g (2.63 mmol, 62%) of the title compound.
IR (film): 3400 cm.sup.-1 : OH, 2940: aliphatic C--H 1430: t-C.sub.4 H.sub.9, 1250: P.dbd.O, 1030+980: P--O--C.
MS: (m/e): 608 (M.sup.+), 371, 288 (100%), 152.
EXAMPLE 20 (COMPOUND 24)
2-(3,5-ditertiarybutyl-4-hydroxyphenyl(ethylidene-1,1-bis (2-oxo-1,3,2-dioxaphosphorinan) ##STR29##
Treatment of tetraethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)ethylidene-1,1-diphosphonate with BrSiMe.sub.3 gave the corresponding tetrakis (trimethylsilyl) diphyosphonate. This latter compound was reacted with PCl.sub.5 in CCl.sub.4 according to the reaction conditions described by T. Morita et al, Chemistry Letters p. 435-438 (1980to afford 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)ethylidene-1,1-diphosphonyl tetrachloride.
To a soltution of Et.sub.3 N (7.86 g, 78 mmol) in 80 ml dioxane held at 55.degree. were added simultaneously the above described diphosphonyl tetrachloride (9.0 g, 19 mmol) in 40 ml dioxane and 1,3-propanediol (2.90 g, 38 mmol) in 40 ml dioxane. The reaction mixture was refluxed for 3 h after the end of the addition. The precipitate of Et.sub.3 N.HCl was removed by filtration and the filtrate was purified by column chromatography (SiO.sub.2, CHCl.sub.3 /MeOH 95/5). An amount of 1.35 g (2.9 mmol, 15% yield) of the title compound was obtained.
mp=175.degree.-176.degree. C.
IR (KBr):=3400, 1430, 1260 (P.dbd.O), 1040 (P--O--C)
MS (m/e).sup.+ =474 (M.sup.+), 353 (100%, M-PO.sub.3 (C.sub.3 H.sub.6).sub.2).sup.+. NMR (CDCl.sub.6) .delta.=7.25 and 7.1 (m, 2H): aromatic H, 5.1 (s, 1H):OH 4.45, 4.3 and 4.1 (3m, 8H): P--O--(CH.sub.2)--, 3.26 d.times.t, J=6 and 17 Hz, 2H):Ph--CH.sub.2 --, 2.80 (t.times.t, J=7 and 23 Hz, 1H):Ph--CH.sub.2 -CH, 2.1 and 1.9 (2m, 4H):P--O--CH.sub.2 CH.sub.2 --CH.sub.2, 1.4 (s, 18H):t-C.sub.4 H.sub.9.
EXAMPLE 21 (COMPOUND 43)
Tetraethyl 4-(3,5-ditertiarybutyl-4-hydroxyphenyl)-1,3-butadienylidene-1,1-diphosphonate ##STR30##
Titanium tetrachloride (3.14 g, 0.017 mol) was dropped, under nitrogen, to 40 ml of anhydrous THF cooled in an ice bath. It was successively added 2.15 g (0.008 mol) of 3,5-ditertiarybutyl-4-hydroxy-cinnamaldehyde, 2.39 g (0.008 mol) of tetraethyl methylenediphosphonate and 3.25 g (0.033 mol) of methylmorpholine. The resulting mixture was kept in the ice bath for a further 1 hour than allowed to return to room temperature overnight. 50 ml of water was added and the resulting mixture was extracted with 3.times.50 ml of ethyl ether. The combined organic phase was washed with 3.times.50 ml of brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (SiO.sub.2, 95/5 CHCl.sub.3 /MeOH) to give 3.6 (0.0068 mol, 82%) of the crude title compound. The latter was recrystallized from acetone yielding 2.1 g (0.0040 mol, 48%) of pure product. Melting point was 141.degree.-143.degree. C. giving a deep red solution.
IR (KBr): 3360 cm.sup.-1 : OH, 1600, 1550 and 1530: C.dbd.C, 1420 and 1430: tS.sub.4 H.sub.9 1200: P.dbd.O, 1020: P--O--C.
MS: m/e 530 (M.sup.+), 515 (M-Me), 393 (M-PO.sub.3 Et.sub.2).
NMR (CDCl.sub.3): .delta.=8.05-7.7 (several m, 2H): C.dbd.CH--CH.dbd.C, 7.4 (s, 2H): aromatic H, 7.04 (d, J=15 Hz, 1H): Ph--CH.dbd.C, 5.6 (s, 1H): OH, 4.2 (m, 8H): P--O--CH.sub.2 CH.sub.3, 1.45 (s, 18H): t-C.sub.4 H.sub.9, 1.35 (t, J=7 Hz, 12H): P--O--CH.sub.2 CH.sub.3.
EXAMPLE 22 (COMPOUND 45)
Diethyl 2-(3,5-ditertiarybutyl-4-hydroxphenyl) 1-(2-oxo-1,3,2-dioxaphosphorin-2-yl)ethenyl-1-phosphonate ##STR31##
Diethyl (2-oxo-1,3,2-dioxaphosphorin-2-yl)methylphosphonate was prepared by the Arbuzov reaction of triethyl phosphite and 2-chloromethyl-2-oxo-1,3,2-dioxaphosphorinan. (IR: 1260 and 1030 cm.sup.-1).
The general reaction conditions described in example 6 were employed using diethyl (2-oxo-1,3,2-dioxaphosphorin-2-yl) methylphosphonate as the phosphonate reagent. After work up, purification by column chromatography gave the title compound as an oil in 63% yield.
IR (Film): 3450 cm.sup.-1, 1570 (C.dbd.C), 1420, 1260, 1030 (P--O--C).
MS: 488 (M.sup.+), 367 (M-PO.sub.3 Et.sub.2).sup.+, 351 (M-PO.sub.3 (CH.sub.2).sub.3).sup.+, 57 (t-Bu).
NMR (CDCl.sub.3):
=8.2 (d.times.d, J=30 and 48 Hz, 1H): Ph--CH.dbd.CP.sub.2, 7.75 (m, 2H): aromatic H, 5.65 (m, 1H): OH, 4.3-4.0 (several m, 8H): P--O--CH.sub.2 --CH.sub.3 and P--O--CH.sub.2 --(CH.sub.2).sub.2, 2.1-1.6 (several m, 2H): P--O--CH.sub.2 --CH.sub.2 --CH.sub.2, 1.4 (s, 18H): t-C.sub.4 H.sub.9, 1.4 (t, J=7 Hz): P--O--CH.sub.2 --CH.sub.3.
EXAMPLE 23 (COMPOUND 28)
Tetraethyl 4-(3,5-ditertiarybutyl-4-hydroxyphenyl)-butylidene-1,1-diphosphonate ##STR32##
0.5 g (0.94 mmol) of tetraethyl 4-(3,5-ditertiarybutyl-4-hydroxyphenyl)-1,3-butadienylidene-1,1-diphosphonate (compound 43), 0.23 g of 10% palladium on active charcoal in 25 ml of glacial acetic acid were submitted to 3 atm. hydrogen gas in a Parr hydrogenation apparatus until no more absorption was observed. The catalyst was filtered. The filtrate was diluted with an equal volume of water and extracted with chloroform. The chloroform phase was washed successively with 10% NaOH, water and dried over MgSO.sub.4. Evaporation of the solvent gave 0.4 g of the title compound (98% purity by GC).
IR (film)=3400 cm.sup.-1 : O--H, 2940: aliphatic C--H, 1440: t-butyl, 1250: P.dbd.O, 1020: P--O--C.
NMR (CDCl.sub.3): .delta.=6.96 (s, 2H): aromatic H, 5.03 (s, 1H): OH, 4.24-4.10 (m, 8H): P--O--CH.sub.2 --CH.sub.3, 2.52 (t, J=7 Hz, 2H): Ph--CH.sub.2 --, 2.28 (t.times.t, J=6 and 24 Hz, 1H): Ph--CH.sub.2 --CH.sub.2 --CH.sub.2 --CHP.sub.2, 2.04-1.78 (2.times.m, 4H): Ph--CH.sub.2 --CH.sub.2 --CH.sub.2 --CHP.sub.2, 1.40 (s, 18H): tC.sub.4 H.sub.9, 1.28 (two overlapping t, J=7 Hz, 12H): P--O--CH.sub.2 --CH.sub.3.
MS: 534 (M.sup.+).
This compound was chromatophically and spectroscopically identical to the material isolated from the reaction of 3-(3,5-ditertiaryl-4-hydroxyphenyl)-propyl bromide (mp=52.degree.-54.degree. C.) with the sodium salt to tetraethyl methylenediphosphonate in benzene.
TABLE 1__________________________________________________________________________Phenol substituted gem-diphosphonates (Ia) ##STR33## (Ia) mp or bp (mmCpd X.sup.1 X.sup.2 X.sup.3 A B Z.sup.1 Z.sup.2 Z.sup.3 Z.sup.4 Hg), .degree.C. Formula.sup.a__________________________________________________________________________1 3-Me 5-t-Bu 4-H CH.sub.2 H OEt OEt OEt OEt 190(0.05) C.sub.21 H.sub.38 O.sub.7 P.sub.22 3-i-Pr 5-i-Pr 4-H CH.sub.2 H OEt OEt OEt OEt 195(0.05) C.sub.22 H.sub.40 O.sub.7 P.sub.23 3-sec-Bu 5-sec-Bu 4-H CH.sub.2 H OEt OEt OEt OEt 200(0.05) C.sub.24 H.sub.44 O.sub.7 P.sub.24 3-t-Bu 5-t-Bu 4-H CH.sub.2 H OEt OEt OEt OEt 62-63 C.sub.24 H.sub.44 O.sub.7 P.sub.25 3-t-Bu 5-t-Bu 4-H S H OEt OEt OEt OEt 78-80 C.sub.23 H.sub.42 O.sub.7 P.sub.2 S6 3-t-Bu 5-t-Bu 4-H CH.sub.2 H OiPr OiPr OiPr OiPr 104-105 C.sub.28 H.sub.52 O.sub.7 P.sub.27 3-t-Bu 5-t-Bu 4-H CH.sub.2 H OnBu OnBu OnBu OnBu b C.sub.32 H.sub.60 O.sub.7 P.sub.28 3-t-Bu 5-t-Bu 4-H CH.sub.2 H OH OH OH OH 177-178 c9 3-t-Bu 5-t-Bu 4-H S H OH OH OH OH 183-185 c10 3-t-Bu 5-t-Bu 4-H CH.sub.2 H OMe OMe OMe OMe 77-78 C.sub.20 H.sub.36 O.sub.7 P.sub.211 3-OMe 5-OMe 4-H CH.sub.2 H OEt OEt OEt OEt b d12 3-OMe 5-OMe 4-Me CH.sub.2 H OEt OEt OEt OEt 205(0.05) C.sub.19 H.sub.34 O.sub.9 P.sub.213 6-Cl 3,4-OCH.sub.2 CH.sub.2 H OEt OEt OEt OEt 200(0.05) C.sub.17 H.sub.27 ClO.sub.8 P.sub.214 3-t-Bu 5-t-Bu H (CH.sub.2).sub.2 H OEt OEt OEt OEt b C.sub.25 H.sub.46 O.sub.7 P.sub.215 3-t-Bu 5-t-Bu Me CH.sub.2 Me OEt OEt OEt OEt b C.sub.26 H.sub.48 O.sub.7 P.sub.216 3-t-Bu 5-t-Bu 4-H SO.sub.2 H OEt OEt OEt OEt 118-120 C.sub.23 H.sub.42 O.sub.9 P.sub.2 S17 3-t-Bu 5-t-Bu 4-H S(CH.sub.2).sub.3 H OEt OEt OEt OEt b d18 3-t-Bu 5-t-Bu 4-H CH.sub.2 H OEt OEt OnBu OnBu b C.sub.28 H.sub.52 O.sub.7 P.sub.219 3-t-Bu 5-t-Bu 4-H CH.sub.2 H OEt OEt NMe.sub.2 NMe.sub.2 b C.sub.24 H.sub.46 N.sub.2 O.sub.5 P.sub.220 3-t-Bu 5-t-Bu 4-H S(CH.sub.2).sub.6 H OEt OEt OEt OEt b C.sub.29 H.sub.54 O.sub.7 P.sub.2 S21 3-t-Bu 5-t-Bu 4-H CH.sub.2 Et OEt OEt OEt OEt 107-110 C.sub.26 H.sub.48 O.sub.7 P.sub.222 3-t-Bu 5-t-Bu 4-H S H OiPr OiPr OiPr OiPr 106-108 C.sub.17 H.sub.50 O.sub.7 P.sub.2 S23 3-t-Bu 5-t-Bu 4-H CH.sub.2 H OnPr OnPr OnPr OnPr 73-74 C.sub.28 H.sub.52 O.sub.7 P.sub.224 3-t-Bu 5-t-Bu 4-H CH.sub.2 H O(CH.sub.2).sub.3O O(CH.sub.2).sub.3 O 173-174 C.sub.22 H.sub.36 O.sub.7 P.sub.225 3-t-Bu 5-t-Bu 4-H CH.sub.2 H OEt OEt OiPr OiPr 59-60 C.sub.26 H.sub.48 O.sub.7 P.sub.226 3-sec-Bu 5-sec-Bu 4-H CH.sub.2 H OiPr OiPr OiPr OiPr b C.sub.28 H.sub.52 O.sub.7 P.sub.227 3-t-Bu 5-t-Bu 4-H CH.sub.2 H OCH .sub.2CMe .sub.2CH.sub.2 O OCH .sub.2CMe .sub.2CH.sub.2 66-67 C.sub.26 H.sub.44 O.sub.7 P.sub.228 3-t-Bu 5-t-Bu 4-H (CH.sub.2).sub.3 H OEt OEt OEt OEt b d29 3-t-Bu 5-t-Bu 4-H CHCHCH.sub.2 H OEt OEt OEt OEt b d__________________________________________________________________________ a = analyzed for C, H, P; results within 0.4% of theoretical values b = purified by column chromatography c = characterized by NaOH titration d = characterized by IR and MS spectroscopies
TABLE 2__________________________________________________________________________Phenol Substituted gem-diphosphonates (Ib) ##STR34## (Ib) mp or bpCompound X.sup.1 X.sup.2 X.sup.3 k d Z.sup.1 Z.sup.2 Z.sup.3 Z.sup.4 (mm Hg), Formula.sup.a__________________________________________________________________________30 3-Me 5-t-Bu 4-H 0 0 OEt OEt OEt OEt b C.sub.21 H.sub.36 O.sub.7 P.sub.231 3-i-Pr 5-i-Pr 4-H 0 0 OEt OEt OEt OEt 97-100 C.sub.22 H.sub.38 O.sub.7 P.sub.232 3-sec-Bu 5-sec-Bu 4-H 0 0 OEt OEt OEt OEt 102-105 C.sub.24 H.sub.42 O.sub.7 P.sub.233 3-t-Bu 5-t-Bu 4-H 0 0 OEt OEt OEt OEt 120-121 C.sub.24 H.sub.42 O.sub.7 P.sub.234 3-t-Bu 5-t-Bu 4-H 0 0 OiPr OiPr OiPr OiPr 131-132 C.sub.28 H.sub.50 O.sub.7 P.sub.235 3-t-Bu 5-t-Bu 4-H 0 0 OnBu OnBu OnBu OnBu 59-61 C.sub.32 H.sub.58 O.sub.7 P.sub.236 3-t-Bu 5-t-Bu 4-H 0 0 OH OH OH OH 135-137 c37 3-OMe 5-OMe 4-H 0 0 OEt OEt OEt OEt 53-55 C.sub.18 H.sub.30 O.sub.9 P.sub.238 H 3,4-OCH.sub.2 0 0 OEt OEt OEt OEt b C.sub.17 H.sub.26 O.sub.8 P.sub.239 H 3,4-O(CH.sub.2).sub.2 0 0 OEt OEt OEt OEt b C.sub.18 H.sub.28 O.sub.8 P.sub.240 3-t-Bu 5-t-Bu 4-Me 0 0 OEt OEt OEt OEt b C.sub.24 H.sub.44 O.sub.7 P.sub.241 3-t-Bu 5-t-Bu 4-MeCO 0 0 OEt OEt OEt OEt b C.sub.26 H.sub.44 O.sub.8 P.sub.242 3-t-Bu 5-t-Bu 4-H 0 0 OEt OEt OBu OBu b C.sub.28 H.sub. 50 O.sub.7 P.sub.243 3-t-Bu 5-t-Bu 4-H 1 0 OEt OEt OEt OEt 141-143 C.sub.26 H.sub.44 O.sub.7 P.sub.244 3-t-Bu 5-t-Bu 4-H 0 2 OEt OEt OEt OEt b d45 3-t-Bu 5-t-Bu 4-H 0 0 O(CH.sub.2).sub.3 O OEt OEt b C.sub.23 H.sub.48 O.sub.7 P.sub.246 3-t-Bu 5-t-Bu 2-H 0 0 OEt OEt OEt OEt 143-145 C.sub.24 H.sub.42 O.sub.7 P.sub.247 3-t-Bu 5-t-Bu 4-H 0 0 OMe OMe OMe OMe 95-96 C.sub.20 H.sub.34 O.sub.7 P.sub.248 3-t-Bu 5-t-Bu 4-H 0 0 OnPr OnPr OnPr OnPr 85-87 C.sub.28 H.sub.50 O.sub.7 P.sub.249 3-t-Bu 5-t-Bu 4-H 0 0 OEt OEt OiPr OiPr 106-107 C.sub.26 H.sub.46 O.sub.7 P.sub.250 3-sec-Bu 5-sec-Bu 4-H 0 0 OiPr OiPr OiPr OiPr b C.sub.28 H.sub.50 O.sub.7 P.sub.251 3-t-Bu 5-t-Bu 4-H 0 0 O(CH.sub.2).sub.3 O O(CH.sub.2).sub.3 O 207-213 C.sub.22 H.sub.34 O.sub.7 P.sub.2__________________________________________________________________________ a = analyzed for C, H, P; results within 0.4% of theoretical values b = purified by column chromatography c = characterized by IR and MS spectroscopies d = characterized by IR and MS specroscopies
PHARMACOLOGICAL ACTIVITY OF GEM-DIPHOSPHONATES OF FORMULA (I)
During routine screening the gem-diphosphonate derivatives were discovered to display a spectrum of pharmacological activities, the most marked being hypolipidemia (hypocholesterolemia and/or hypotriglyceridemia). Some of the diphosphonic acid derivatives demonstrated anti-inflammatory activity and some diphosphonate esters were hypotensive. Diuretic and positive inotropic activity were also observed.
In addition it might be expected that the gem-diphosphonates posses antioxidant and radical scavenging activities associated with the dialkyl hydroxyphenyl moieties present in their structures. Free radical scavengers are known to be efficacious in preventing the pathological changes in a number of diseases induced by oxidative stress. The gem-diphosphonates are thus potentially useful for the treatment of diseases such as:
tissue ischemia such as heart and brain ischemia,
muscular dystrophy,
chronic obstructive pulmonary disease,
viral infections,
senile caractogenesis and
vitamin E deficiencies.
A) HYPOLIPIDEMIC ACTIVITY
With the goal of finding new drugs which might be hypolipidemic, the new diphosphonates described in this patent application were administered orally to mice. This rodent species has plasma lipid level relatively close to man (generally greater than 150 mg/dl). For example, in mice receiving a normal diet the plasma cholesterol and triglyceride levels are in the range of 100 mg/dl, whereas for rat the comparative values are close to 50 mg/dl. Other scientists have recently investigated the use of mice and found this species to be a relevant model for testing new agents in comparison to drugs known to be efficacious in human hyperlipidemia (Effects of Fenofibrate, Gemfibrozil and Nicotinic Acid and Plasma Lipoprotein Levels in Normal and Hyperlipidemic Mice, a Proposed Model for Drug Screening. Olivier, P. et al. Atherosclerosis 70, p. 107-114, 1988).
1) Methods
In every screening experiment, 30 mice of the OF1 strain weighing 25 to 35 g were divided into 5 groups of 6 animals each. Four groups received the compounds to be tested, or the reference drugs, the fifth group served as control. Compounds were dissolved in diethyl ether, and solution was added to the pelleted food and the ether was evaporated.
All compounds were tested at the final concentration of 0.1% in animal chow, equivalent to a daily intake of about 180 mg/kg. This diet was fed for 10 days, then after an overnight fasting the animals were sacrified by decapitation under ether anesthesia. Blood samples were collected in EDTA containing tubes.
Plasma cholesterol and plasma triglycerides were measured by enzymatic methods (Ames kit No. 6376 and No. 6630). The mean cholesterol or triglycerinde value of each group receiving tested compounds or reference drugs was expressed as percent of the mean value observed for the contemporary control.
2) Results
Table 3 showed that a number of diphosphate derivatives (Compounds 3, 4, 5, 6, 7, 18, 21, 22, 23, 24, 33, 34, 37, 47 and (48) were marked by hypocholesterolemic, Compounds 33 and 34 being the most potent (-40%) and -41%). Clofibrate, gemfibrozil and fenofibrate, drugs used clinically for the treatment of hyperlipidemia, were found to be less hypocholesterolemic than many of the diphosphonates tested. Fenofibrate was the most potent (-15%) of the reference drugs tested. Similar hypocholesterolemic activity was measured in the mice receiving the fibrate derivatives as published in the reference cited above (Olivier, P. et. al.).
A significant hypotriglyceridemia was observed with Compounds 3, 5, 6, 7, 21, 22, 23, 24, 30, 31, 33, 37, 47 and 48. It should be noted that Compounds 3, 19, 24, 30, 37 and 47 decreased plasma triglycerides by more than 44%, values not reached by the reference drugs tested similarly. Gemfibrozil was the most potent hypotriglyceridemic reference drug (-35%), which is in accordance with values published in the literature.
The exact mechanism by which these diphosphanates lower plasma lipids in various in vivo models is not known. However, investigations using in vitro preparations have demonstrated that these compounds inhibit and interfere with some key enzymes involved in cholesterol synthesis and metabolism, specifically acyl-CoA: cholesterol acyltransferase (ACAT), lipases, etc., and thus indicate the possible sites of action.
B) ANTI-INFLAMMATORY ACTIVITY cl 1) Methods
The effect of four selected diphosphates was investigated on the inflammatory response to kappa carrageenan in the rat paw oedema model. Eight male rats were employed per group. Oedema was induced in the right hind paw of each animal by a single injection into the plantar aponeurosis of 0.1 ml of a 1% w/v of kappa carrageena solution dissolved in 0.9% NaCl. The test compounds (100 mg/kg) and reference drug (indomethacin 30 mg/kg) were administered by gavage 1 hour prior to induction of oedema by carrageanan injection.
The volume of the right paw was measured for each animal at 0, 1, 2.5 and 4 hours after carrageenan injection (only 4 hour values are reported.
2) Results
Table 4 showed that indomethacin prevented completely the increase in paw volume as expected. Compounds 8 and 36 showed significant inhibitory activities whereas their ethyl ester counterparts demonstrated only minimal activity.
These results indicate that the diphosphonic acids such as Compound 8 are anti-inflammatory in this animal model.
C) ORAL HYPOTENSIVE ACTIVITY IN HYPERTENSIVE RATS
The spontaneously hypertensive rat (SHR) is a well established animal model of human arterial hypertension. The gem-diphosphonates of formula (I) were found to induce a marked hypotension when administered to SHRs.
In screening experiments various gem-diphosphonates were dissolved in Tween-80 and administered orally to SH rats. Blood pressure was monitored hourly using a tailcuff method. Hypotensioln measured two hours post dose are given in Table 5.
Compounds 4, 6, 7 and 18 decreased blood pressure by 30 to 50% and are as potent as the reference drugs tested similarly and which are used for the treatment of angina pectoris and hypertension.
The gem-diphosphates of formula (I) are thus potentially useful in the treatment of cardiovascular diseases via a smooth muscle relaxant activity. The primary indications of these compounds would be the treatment of angina pectoris, congestive heart failure and hypertension.
TABLE 3______________________________________HYPOLIPIDEMIC ACTIVITY OF DIPHOSPHONATESOF FORMULA (I) AND REFERENCE DRUGS Cholesterol Triglycerides (% control) (% control)______________________________________Compounds(I) 1 -2 -28 2 +6 -17 4 -12 -1 6 -37 -34 7 -23 -15 8 -2 +1910 -5 -1919 -6 -44 3 -19 -46 5 -22 -2433 -40 -2130 +2 -4531 +4 -1135 0 +736 -9 -538 -5 -613 -5 +3818 -31 +6020 +5 +1321 -16 -2822 -21 -3723 -15 -3324 -20 -7132 +8 +934 -41 +1137 -16 -7039 +4 +1741 -3 +642 +12 +143 -5 -1446 +1 -1247 -31 -4548 -21 -36Reference DrugsClofibrate +4 -5Gemfibrozil -7 -35Fenofibrate -15 -2______________________________________
TABLE 4______________________________________ANTI-INFLAMMATORY ACTIVITYOF DIPHOSPHONATES OF FORMULA (I) ANDINDOMETHACINInhibition of rat right hind paw volume increase(4 hours post oedema induction) % Change from control______________________________________Compounds (I)Compound 4 +1.5Compound 8 -54.2Compound 33 -5.8Compound 36 -25.0Reference Drug -92.3Indomethacin______________________________________
TABLE 5______________________________________EFFECT OF GEM-DIPHOSPHONATES OF FORMULA (I)ON BLOOD PRESSURE IN HYPERTENSIVE RATS(2 hours post dose) Percent decrease in blood pressure______________________________________Compounds(I)4 -346 -647 -3018 -413 -20Reference DrugsDiltiazem -38Nifedipine -47______________________________________
MODES OF ADMINISTRATION
The gem-diphosphonates of formula (I) can thus be used for the treatment of hyperlipidemia and/or hypertension and can be administered preferably in the form of capsules, tablets and granules. For this purpose the active principle should be mixed with a pharmaceutical carrier.
As used herein, the term "pharmaceutical carrier" denotes a solid or liquid filler diluent or encapsulating substance. Some examples of the substances which can serve as pharmaceutical carriers are sugars, starches, cellulose and its derivative, powdered tragacanth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils, polyols and polyethylene glycol, agar, alginic acid, pyrogen-free water, isotonic saline and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents and lubricants such as sodium lauryl sulfates, as well as coloring agents, flavoring agents and preservatives, can also be present.
The pharmaceutical carrier employed in conjunction with the phosphonates is used at a concentration sufficient to provide a practical size to dosage relationship. Preferably the pharmaceutical carrier comprises from about 0.1% to 99% by weight of the total composition. Capsules and tablets are prepared by conventional methods using gem-diphosphonates in their liquid or cristalline form as described in the following examples:
______________________________________Example of a Capsule FormulationIngredients mg/Capsule______________________________________Compound 7 300Gelatin 100Polyethylene glycol 1000 600Potassium sorbate 0.5______________________________________Example of a Tablet FormulationIngredients mg/Tablet______________________________________Compound 33 500Hydroxypropyl- 500methyl celluloseMagnesium stearate 3______________________________________
For the treatment of specific disease states, composition containing a pharmaceutically acceptable gem-diphosphonate can be administered as a solution, suspension, emulsion or by intradermal, intramuscular, intravenous or intraperitoneal injection. Rectal administration of gem-diphosphonates can be performed by incorporating the active principle into conventional jelly bases to produce suppositories.
Claims
  • 1. A method for lowering plasma lipid levels in hyperlipidemic patients for the treatment of atherosclerotic disease comprising administering to a patient in need of same an effective amount of a phenol substituted gem-diphosphonate derivative of formula (I) ##STR35## where Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 indentical or different are
  • OR where R is H, or a straight or branched alkyl group comprising from 1 to 4 carbon atoms,
  • or where Z.sup.1 with Z.sup.2 or Z.sup.3 with Z.sup.4 may form an alkylidenedioxy ring comprising from 3 to 5 carbon atoms,
  • X.sup.1, X.sup.2 identical or different, are a straight or branched alkyl group from 1 to 4 carbon atoms,
  • A is S, (CH.sub.2), or (CH.dbd.CH).sub.k --CH.dbd. where n is an integer from 1 to 3, and k is zero or 1,
  • B is H, or an alkyl group from 1 to 2 carbon atoms,
  • t is zero or 1, with the proviso that t is zero only when A is (CH.dbd.CH).sub.k --CH.dbd. were k is as described above, said amount being effective to lower plasma lipid levels in said patient.
  • 2. A method as claimed in claim 1, wherein said diphosphonate derivative is tetraethyl 2-(3,5-di-secondarybutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonate.
  • 3. A method as claimed in claim 1, wherein said diphosphonate derivative is tetraisopropyl (2-3,5-ditertiarylbutyl-4-hydroxyphenyl)ethylidene-1,1-diphosphonate.
  • 4. A method as claimed in claim 1, wherein said diphosphonate derivate is tetrabutyl 2-(2-3,5-ditertiarylbutyl-4-hydrophenyl)-ethylidene-1,1-diphosphonate.
  • 5. A method as claimed in claim 1, wherein said diphosphonate derivative is tetraethyl 2-(3,5-ditertiarylbutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonate.
  • 6. A method as claimed in claim 1, wherein said diphosphonate derivative is tetraethyl 3,5-ditertiarybutyl-4-hydroxyphenylthio-methylene diphosphonate.
  • 7. A method as claimed in claim 1, wherein said diphosphonate derivative is (2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethylidine-1,1-bis (2-oxo-1,3,2-dioxaphosphorinan).
  • 8. A method as claimed in claim 1, wherein said diphosphonate derivative is 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonic acid.
  • 9. A method as claimed in claim 1, wherein said diphosphonate derivative is tetraethyl 2-(3-tertiarybutyl-4-hydroxy-5-methylphenyl)-ethenylidene-1,1-diphosphonate.
  • 10. A method as claimed in claim 1, wherein said diphosphonate derivative is tetraethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethenylidene-1,1-diphosphonate.
  • 11. A method as claimed in claim 1, wherein said diphosphonate derivative is tetraisopropyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)ethenylidene-1,1-diphosphonate.
  • 12. A method as claimed in claim 1, wherein said diphosphonate derivative is tetramethyl 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethenylidene-1,-diphosphonate.
  • 13. A method as claimed in claim 1, wherein said diphosphonate derivative is 2-(3,5-ditertiarybutyl-4-hydroxyphenyl)-ethenylidene-1,1-diphosphonic acid.
  • 14. A method as claimed in claim 1, wherein said diphosphonate derivative is tetra-n-propyl 2-(3,5-di-t-butyl-4-hydroxyphenyl)-ethylidene-1,1-diphosphonate.
  • 15. A method as claimed in claim 1, wherein said diphosphonate derivative is tetra-b-butyl 2-(3,5-di-t-butyl-4-hydroxyphenyl)-ethenylidene-1,1-diphosphonate.
  • 16. A method as claimed in claim 1, wherein said diphosphonate derivative is tetra-n-propyl 2-(3,5-di-t-butyl-4-hydroxyphenyl)-ethenylidene-1,1-diphosphonate.
  • 17. A method as claimed in claim 1, wherein said diphosphonate derivative is tetra-isopropyl 3,5-di-t-butyl-4-hydroxyphenylthio-methylene-diphosphonate.
  • 18. A method as claimed in claim 1, wherein said diphosphonate derivative is embodied in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier.
  • 19. A method according to claim 18, wherein said diphosphonate derivative is tetraethyl 2-(3,5-di-t-butyl-4-hydroxyphenyl)ethenylidene-1,1-diphosphonate.
Priority Claims (1)
Number Date Country Kind
1239/88 Mar 1988 CHX
Parent Case Info

This application is a division of application Ser. No. 07/323,334, filed Mar. 14, 1989 now U.S. Pat. No. 5,043,330.

US Referenced Citations (6)
Number Name Date Kind
3299123 Fitch et al. Jan 1967
3404178 Roy Oct 1968
4309364 Bentzen et al. Jan 1982
4371527 Bentzen et al. Feb 1983
4416877 Bentzen et al. Nov 1983
4696920 Bentzen Sep 1987
Foreign Referenced Citations (4)
Number Date Country
15370 Sep 1980 EPX
1173041 Mar 1986 EPX
100718 Oct 1987 EPX
2043072 Oct 1980 GBX
Non-Patent Literature Citations (7)
Entry
Gross et al., J. fur frakt. Chemie. Band 317, (6), 1975, pp. 890-896.
Gross et al., J. fur prakt. Chemie. Band 320, (2), 1978, pp. 344-350.
Insull et al., JAMA, Jan. 29, 1984, 251(3), pp. 351-364.
Insull et al., JAMA, 1984, 251, pp. 365-374.
Rack et al., New Eng. J. Med., 317(20), 1987.
Lehnept, Tetrahedron 30, pp. 301-305, 1984.
Frick et al., New Eng. J. Med., 317(20), 1987, pp. 1237-1245.
Divisions (1)
Number Date Country
Parent 323334 Mar 1989