JPH07506121A - Substituted phosphonates, their preparation and pharmaceutical compositions containing the compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Substituted phosphonates, processes for their preparation and pharmaceutical compositions containing the compounds The present invention relates to This invention relates to a novel phosphonate substituted with a kylphenol group and a method for producing the same. Sara The present invention relates to pharmaceutical compositions containing these compounds and reactive oxygen gases/cals. therapeutic use in related diseases, more specifically in the treatment of atherosclerosis. Regarding use in medical treatment.

Reactive oxygen species have been linked to many pathological conditions, which have led to pharmacological and clinical The following symptoms have been clinically proven ()\Hallive [Free radicals and catalytic metal ions in human diseases] On's Role Ohmashi'', Methods Enzymol (Methods Enz ymol, ) 18th, 1-85.1 - Inflammation and immunological damage (autoimmune diseases) rheumatoid arthritis), - ischemic/recurrent injury, One radiation ti wound, premature aging, - Parkinson and Alzheimer's disease, - cancer and anti-cancer treatment, Like intermittent waves, excessive platelet aggregation, myocardial infarction and atherosclerosis. Symptoms associated with disorders of the blood circulation system In these pathologies, antioxidants are useful as therapeutic agents. To the inventors A test conducted by It exhibits strong antioxidant activity through the sulfonate group, thus providing therapeutic efficacy. This suggests that

In individual cases of atherosclerosis, today the collection retained in LDL Sterols are the most atherogenic form of plasma cholesterol has been proven. On the other hand, recent studies have focused on the uptake of oxidized LDL by macrophages. The shape of lipid-loaded foam cells formation, and its formation is the first step in the development of atherosclerosis. It is clear that Today, many epidemiological studies have shown that high blood cholesterol has been established as a major risk factor for coronary heart disease. The above experiment Based on the It can be assumed that the latter case is more effective than the other case. Therefore, dual hypocholesterolemia Drugs with anti-inflammatory and antioxidant properties are of interest in the treatment of atherosclerosis. It can be said that it is very effective.

The phosphonate compound (1) of the present invention is a potent hypocholesterolemic agent in humans. HMGCoA reductase enzyme inhibitors (lovastatin, numvastatin) :/ (lovastatin, simvastatin)) significantly inhibits cholesterol synthesis in cell lines. Its antioxidant and low cholesterol The combination of rolytic activity makes the phosphonates of the present invention effective in treating high cholesterol. It has the efficacy to treat diseases associated with 1 degree lipid oxidation and pathological lipid oxidation. Ru. Furthermore, due to the lipophilic nature of these compounds, they are incorporated into LDL, It is expected to protect these particles from damage caused by the oxidizing electrode.

The compound of the present invention has the structural formula (1) [In the formula, Xl and Xl are the same or different and are a 1i chain or a branched C+Cs alkyl group and -)゛ is O or S, -71, Z2 are the same or different, -OR(::l:, RflH, KNuf : is a branched C + Ca 7 + Ru group), -NR'RI (where R1, R 1 are the same or different, H or a linear or branched C, -C, alkyl group, Even if Zl and Z2 come together to form a CmCs alkylidenedioxy group, often, -G is OH or its bioprogenitor group, -D is saturated or unsaturated c, CI+a of which one or more methylene groups are sulfur atoms, oxygen atoms carbonyl group, optionally l or more methyl Ren group is one or more halogen atoms (F, C1 or Br), C1-5 even if substituted by alkyl, phenyl, hydroxy or acyloxy groups good〕 and its salts, solvates and hydrates.

Preferably Xl and I2 are the same and are butyl groups, especially t-butyl groups .

Preferably Y is oxygen.

Preferably, Zl and Z2 are identical, especially OR, where R is Hl or WL chain or branched C1,. alkyl group). More preferably Zl and and Z2 are the same OR group (wherein R is CI4alkyl, especially methyl, ethyl or is isopropyl).

Preferably G is OH.

Suitable bioprogenitor groups for the OH group as defined for G include, for example, the OR3 group (where R3 is 1i brass or branched C, -C, alkyl group, perfluorinated C 1-06 alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted benzyl group suitable bioprecursor groups also include the R3-C(0)O- group, the Rco0-C(0 )O- group, R3NH-C(○)○- group, R''C(0)○CH20- group, R3-5 It can be an OtO- group (wherein R3 is the same as above).

Preferably, D is AC(0)B, ACH(OH)BSA-CHtB.

(CHt)t (CH=C)()n (CHz)t or 5-(CH2)t , where -A is (CHt)t, (CH=CH)n CH=CX3, (CHx )t CHX', S (CHz)t (CH=CH)n, S CX'X', (C H=CH)n-CH=CH-C(0)-CHX', (C)h)pCH=CHC (0)-CHX', (CHt)t-C(0)-CHX', 5-(CHz)t ( CH=Ct()n-C(0) CHX', 5-CX'X5-C(0)-C1-I X3, (CH=CH)n-CH=CH-CH(OH)-CHX3, (CH2)I )CH=CH-CH(OH)CHX', (CHz)t-CH(OH)-CHX3 , S (CH2)t-(CH=CH)n-CH(OH)CHX3.5-CX"X '-CH(OH)-CHX', where n is 0.1 or 2, and the tip is θ ~4, and p is a number from 1 to 3.

-X3 is H, II! Chain or branched CI Ca alkyl group, substituted or unsubstituted is a phenyl group, -X', I5 are the same or different, H,, linear or branched C+Ca alkyl is the basis, B is CHHz, CH-X', X'-C-X' (connie, x' and x' are Same mataha different, halogen atom (F, CI, Br), straight or branched c, - Cs alkyl group, substituted or unsubstituted phenyl group).

A is (CH,)t, (CH=CH)n-CH=CX3, (CHz)t-CHX' , S (CHz)t (CH=CH)n, S CX'X5, then B is also CH=CH(CHt)p, CH=C, H-C) (X', CH=CH-CX@X? p, I6 and I7 are the same as above.

Preferably, D can also be A'-CH(○-Co-X8)-B', Two 8 “is (CH,)t, (CH=CH)n-CH=CX3, (CHz)t CHX3.5-(CH,)t-(CH=CH)n, 5-CX"X', Bo is CH2, CH-X', X'-C-X', C) (=CH-(CHt)pSCH= CH-CHX@, CH=CH-CX'X'teJ'), t, nSp, Xs, I4, I5, X@ and IJX' are the same as in M, and Xs is saturated or unsaturated. C, -C, alkyl or alkenyl chain.

Suitable salts contemplated within formula (1) include, for example, OR (in Zl/Z2) Corresponding salts of groups, e.g. alkali metal elements such as sodium or potassium 1 It includes salts formed from D.

Method for producing compound of formula (+) The present invention also relates to methods used to produce substituted phosphonates (■).

If D is He C(○)-B A: (CHz)t, (CH=CH)n CH=CX3, (Ct-h)t-CH X”, S (CHz)t-(CH=CH)n or 5-cx’xgB: CH , , CH-X' or c-xgx The method described in Fig. 1 (page 10) Commercially available alkyl phosdecinate It consists of reacting with a suitable base such as thiamine isopropylamide. One Then, the lithium anion of compound m thus formed is treated with an appropriate ion in the system. Reaction with ster ■ gives substituted phosphonate (summer). The reaction in an ethereal solvent such as THF or tetrahydrofuran (THF), preferably Perform in THF at 1 degree between -78<0>C and room temperature (25<0>C).

Another operation described in Fig. 2 (page 11) uses titanium tetrachloride as the condensing agent. and N-methylmorpholine to convert the unsaturated aldehyde It consists of condensation with a phosphonate. The reaction is carried out using tetrahydrofuran, diio in an ethereal solvent such as xane or nomethocinoethane, preferably in THF, It is carried out at a temperature between -30°C and the boiling point of the solvent (66°C in the case of THF). Formula (1) A compound (where A is (CH=CH)n-CH=CX") is obtained. Formula (1) The compound (where A is (CH2)t-CHX”) is the starting compound ketophosphorus. It can be produced by reacting nate V with an excess of base or a combination of bases. Ru. The base is sodium hydride, sodium alkoxide, n-butyllithium Or tritium neuisopropylamide. Then, the thus formed keto The anion of phosphonate v is replaced with halide ■ (here, Hal is Br or C1). Make it react.

The reaction is carried out using tetrahydrofuran/methquinethane, dioxane, benzene or is carried out in toluene. The reaction temperature varies between 0°C and the boiling point of the solvent.

Furthermore, Examples 1.2.3 and 4 are experimental embodiments of the method described in FIG. Explain.

For the condensation reaction, if B is a CH2 group, i.e. the phosphonate functionality On the other hand, if the α-position carbon has two protons, then by polycondensation at the γ-position, In addition to the main reaction products formed, further dialkylphenol at α and γ-positions By-products are formed by condensation with the metal group (see Examples 1 and 21t). B is CHX' or x'-c-x7, for example, two protons are in the α-position is not available, the compound formed by polycondensation at the γ-position is the only reactant. (See Examples 4 and 10).

Similarly, if the α-position is not substituted at all (B=CHt), the polyaddition reaction In addition to the main reaction compound formed, by two further additions at the α and γ-positions A resulting by-product is formed (see Example 3).

A: (CH=CH)n-CH=CH-C(0)-CHX', (CHt)p- CH=CH-C(○)-CHX3, (CHt)t-C(0)-CHX', 5( CHt) -(CH=CH)n-C(0)-CHX'? :1tS-CX'X' -C(0)-CHX'B: CH2, CH-X' or c-x'x'Fig, 3 (page 12), the ester of formula consisting of condensation with a dianion of nate V. The dianion is with an equivalent amount of sodium hydride in lahydrofuran at a temperature between -30°C and 30°C. , an excess of a stronger base, such as n-butyllithium or lithium diisopropylene. Obtained by stepwise reaction with pyramide (LDA). too much was reacted with ester ■ once between -70°C and 30°C, and F Ketophosphonate (I) is obtained according to ig, 3.

Compound (1), which has two ketone groups in its structure, has an enol form and a flat form in a solution. Equivalent tautomers may also be used. Noketone and eno of the compound of formula (1) The round shape is part of the invention.

A: (CHs)t, (CH=CH)n CH=CX', (CHx)t-CH X3.5(CH2)t (CH=CH)n or 5-CX4X'B: CH= A compound of the formula ([) with CH-CX'X or CH=CH(CHt), wherein D is A-C(0)-B, and A is (CHt)t.

(CH-CH)n-CH=CX3, (CHz)t-CHX", 5(CHt)t (CH=CH)n or 5-cx'x't', B is CH=CH-CX'X ;IEV: is CH=CH-(CHz)l) The method for producing a compound is the formula ■a or ■ The aldehyde represented by b. is converted into a phosphonate compound of formula ■ or a phosphonate of formula X. It consists of reacting with a phosphorous reagent, which is a salt of sodium.

The reaction is carried out in an ethereal solvent such as dimethoquinoethane or tetrahydrofuran. , in the presence of a base such as sodium hydride or tritium neuisopropylamine It will be carried out.

When D is A-CH(○H)-B The ketophosphonates of formula (+) described above are derived from the corresponding hydroxyphosphonates. It can be returned to the body. The reduction involves sodium borohydride, lithium borohydride, Sodium bis(2-methoxynoethquine)aluminum hydride, borohydride Complex hydrides such as rimethoquinosodium, sodium noanhydride borohydride It can be done with reagents.

Suitable solvents include ether, tetrahydrofuran, toluene, methanol, ethanol. includes tools and isopropanol. Preferred reducing conditions are -2 using sodium borohydride at temperatures between 0°C and 65°C.

When D is A'-CH(0-Co-X')-B', the above hydroxyphosphonate The corresponding anoloxy/-phosphonate derivative can be prepared by using known techniques. Can be esterified into conductors. Appropriate reaction conditions include adding a hydroxyphosphonate to a tertiary a suitable acid anhydride (e.g. triethylamine or pyridine) (X'-Co)go) or an appropriate acid chloride (X''C0-01). It encompasses things. The reaction temperature can be between 0°C and the boiling point of the annulating agent. .

Ketophosphonate (1) is a hydrogenated p-toluenesulfonylhydrazone derivative. with sodium boron, sodium noanhydroborohydride or catecholborane By reduction, the corresponding alkylphosphonates and alkenylphosphonates can be reduced to

Phosphone @ (Z’=Zl=OH) of structural formula (1) is the corresponding phosphonic acid ester By reaction with bromotrimethyl 7rane, bis(trimethylsilyl) phosphatide was obtained. Produced by obtaining sulfonate and reacting it with water or methanol in the system. Can be built.

The starting compound, alkylphosphonate II, is commercially available. starting compound The phosphonate compound ■ was prepared using known literature methods: E.J. Collie and G. Chee Kwiatkotsky (E, J, Corey and G, T, Kv iatkowski), Journal on American Chemical Society Tea (J, ＾誼Chew.Soc, ), ≦10.6816-6821 pages (1 968) and F. Mazey and P. Savinak - p. 654 (1978). Therefore manufactured.

The structure of the new compound of formula (1) was determined by infrared (IR), mass (MS) and nuclear magnetic resonance. Determined by NMR spectroscopy. The purity of the compound was determined by elemental analysis and chroma chromatography, thin layer chromatography, gas-liquid chromatography or Confirm by high performance liquid chromatography.

The abbreviations used in this specification are as follows. In the table, n- is normal -1i- is Iso-1sec- is secondary-1t- is tar/yari-. NMR spectrum where S is a single line, d is a doublet, t is a triplet, and m is a multiplet. The temperature is Expressed in degrees Celsius, melting points are uncorrected.

The present invention will be further illustrated by Examples 1 to 22, which are typical synthetic procedures.

FIG 1 Synthesis method A −+CH21t, fcH-CH1°-CH-C-X3. +CM21L-CH X3,5-(C)+21. -(c)1-C)Il, 1#1Ir-CX'X5 B -CH2, CH-X6tt2i*c-X6X7FIG2・Synthesis method II) ^-1c) l-CHI, -CH-CX'+11 ^-1cH, I, -C I(X FI03 Synthesis method In the formula, EcII-CHI n-C11-C)l, +cH2+p-co*c H5LCH21t IS+C1421t-+C1("CHI@H Mari1js-C X’X51”j5le.

Example 1 /methyl 1,5-bis(3,5-not-tert-butyl-4-hydroxyphenylene) )-3-oxo-1,4-pentadien-2-ylphosphonate and 4-(3,5-tert-butyl-4-hydroxyphenyl)-2 -Oxo-3-buten-1-ylphosphonate titanium tetrachloride (114,5 g, 0 ．． 6 mol) in dry tetrahydrofuran (THF) kept at -20°C under nitrogen. (300 ml) with stirring.

3.5-not-tert-butyl-4-hydroxybenzaldehyde solid (58, 7g.

025 mol), followed by THF (200 ml), then dimethyl 2- Oxopropylphosphonate (50g, 0.3mol) was added. Finally, N-Me Chilmorpholine (121.7 g, 1.2 mol) was slowly introduced into the reaction mixture. was stirred at room temperature for 1 hour. Cold water (200 ml) was introduced and the mixture was diluted with diethyl ether. Extracted with tel (1000 ml). Wash the ether fraction with water to neutral pH. The solution was washed, dried over magnesium sulfate and evaporated under reduced pressure. Chloroform/methano chromatography on a Nori gel using Refined.

The first compound (5.5 g, 4%) eluted from the column was added to dimethyl 1,5-bis (3,5-not-tert-butyl-4-hydroxyphenyl)-3-oxo-pe It was identified as ntanoen-2-ylphosphonate.

Elemental analysis as C3sHs+OgP Calculated value (%) C, 70, 21H, 8, 59P, 5.17Δ1 set stone 1 (%) C, 69,96H, 8,55P, 5.31 Melting point 190-191℃ IR (KBr): 3620cm” (CH), 1610 (C=O), 158 0 (C=C), 1430 and 1420 (t-Bu), 1240 (P=O ), 1020 (P-0-C) MS: m/e=599 (M"+1), 598 (M4), 488 (M' HPOsMe2), 367 (100%) NMR (CDC13) δ=7.75 (d, J=26Hz, IH): Ph-CH FujiC-P7.57 ( d, J-16Hz, IH): Ph-CH=CH-73 and 7.23 (2s, each 28) ・Aromatic H6,60 (d, J=16Hz, LH): Ph-CH=CH 5,55 and 5.51 (2s, each IH): OH3,82 (d, J-11Hz, 6H): P-0-CHsl 40 and 1.34 (2s, each 18H): t The second CaHs compound (36 g, 38% yield) was analyzed by IRSMS and NMR. dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl) It was identified as -2-oxo-3-buten-1-ylphosphonate.

-Bu Melting, Tun 107-109℃ (Ligroin, 80-95 fraction) IR (KB r): 3420cm” (OH), 1650 (C=O), 1590 (C -C), 1420 (t-Bu), 1260 (P=O), and 103 0 (P-0-C) ~Is (m/e): 382 (M’), 367 (M”-Me), 272 (M”-HP ○sMez), 259 (M’-CHzPOsMe+) , 151 (~I”-Co-CHzPOoMet) NMR (CDC13) δ=7.61 (d, J=16Hz, IH): Ph-CH=CH7,42(s , 2H): aromatic H 6,73 (d, J=16Hz, IH): Ph-CH=CH5,62 (s, LH ):OH 3,81 (d, J=11Hz, 6H): P-0-CH.

3.35 (dl=22Hz, 2H) ・CH, -Pl, 40 (s, 18H) ・t-C,H.

Elemental analysis C2゜Hs lOs Calculated value as P (%) C, 62, 81H, 8 , 17P, 8.10 Measured value (%') C, 62, 63H, 7, 97P, 8.24 and Titanium tetrachloride (137.1 g, 0.72 mol) was dissolved in dry THF (3 00ml). 3.5-not-tert-butyl-4-hydroxyben Dulaldehyde (70.4 g, 0.30 mol) was added followed by diethyl Pyrphosphonate (70 g, 0.36 mol) was added. N-methylmorpholy (1458 g, 144 mol) was introduced and the reaction mixture was stirred at room temperature for 2 hours.

By adding water (200ml) and/ethyl ether (800ml) Post-processing was performed. The ether phase was washed with water to neutral pH, dried over MgO, Evaporated. Using CHC1x/MeOH (98/2) as the eluent Chromatography was performed on Lyri gel.

The first product eluted (15 g, 8% yield) was purified by diethyl 1,5-bis(3,5 -7-tert-butyl-4-hydroxyphenyl)-3-oxo-pentaje It was identified as phosphonate.

Elemental analysis C37H530, as P Calculated value (%) C, 70, 90H, 8, 84P, 4.94 measurement 11i (%) C , 71, 18H, 8, 67P, 4.75 melting ton 174-175℃ IR (KBr): 3620cm-' (OH), 1640 (C=O), 1 585 (C=C), 1430 and 1415 (t-Bu), 1230 (P =O) and 1030 (P-0-C) ~Is: m/e-626 (M-), 488 (M--HPOsEh), 39 5 (100%) N~IR (CDC13) 6=7.7 (d, J=26Hz, 2H): Ph-CH=C-P7, 59 ( d, J = 16Hz, 2H): Ph-CH=CH7,30 and 7. 25 (2s, 28 each) Aromatic H6,63 (d, J-16Hz, 2H): P h-CH=CH554 and 5.48 (2s, each IH):OH418 (triple line, J=7Hz, 4H): P OCH=CH5140 and 1.34 (2s, 1 each 88): t C-891, 34 (t, J=7Hz, 6H): P-〇-CH2 The CHhH2O2 compound was converted into diethyl 4-(3,5-not-tert-butyl-4-hypolymer). Droxyphenyl)-2-oxo-3-buten-1-ylposbonate (44g , yield 36%).

Melting point: 110-111°C (recrystallized from ligroin 80-95 fraction) I R (KBr): 3620 cm-1 (OH), 1680 (C=O), 15 90 (C=CL 1430 and 1415 (t-Bu), 1240 (P=O ), and 1230 (P-C=C) MS (m/e): 411 (M"+1), 410 (M two, 277 (M"- H-P○3Eh), 259 (M”CHzP 0sEh), 57 (100 %, t-Bu”) NMR (CDC13) δ=7.61 (d, J=16Hz, IH): Ph-CH=CH7,40(s , 2H) Aromatic H 6,74 (d, J=16Hz, IH): Ph-CH=CH5,6 (s, LH) CH 4,16(m, 4H): P-C=CH2-CH.

3, 33 (d, J = 23Hz, 2H): CH2Pl, 45 (s, 18H): t-C,H.

1.34 (t, J-7Hz, 6H):P OCH2CHs elemental analysis C2□H s　Os　Total as P) II value (%) C, 64, 37H, 8, 59P, 7 ．． 55 Measured value (%) C, 64, 52H, 8, 65P, 7.36 Example 3 Diethyl 1,5-bis(3,5-tert-butyl-4-hydroxyphenylene) )-3-oxo-2-pentylphosphonate and Diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2 -oxo-1-butylphosphonate Sodium hydride (60% suspended in mineral water fI 1.1.45 g, 36.25 mmol ) in hexane under nitrogen. Pipette the latter into dry THF. (60ml). Diethyl 2-oxopropyl phosphonate (7,0 g, 36 mmol) were introduced. The mixture was stirred at room temperature for 30 minutes and then at 0°C. Next, add n-butyllithium (37.5 mL of 1,6M solution, 60 ml) mol) was added. Finally, 3.5-)-tert-butyl-4-hydroxy Solution of benzyl bromide (9.0 g, 30.1 mmol) in THE (40 ml) was added and the reaction mixture was stirred at room temperature overnight. 15% MCI (150ml) and Work-up was carried out by partitioning between two fractions of ether (150 ml). It was. The ether phase was brought to neutral pH with sodium bicarbonate and saturated sodium chloride. Washed with. After softening, the solvent was evaporated and the crude mixture was subjected to column chromatography ( s102, CHCl3/Ac0Et 8/2).

The first compound eluted (1.5 g, yield ±8%) was extracted from diethyl 1.5-bis (3° 5-tert-butyl-4-hydroxyphenyl)-3-oxo-2-pene It was tylphosphonate. Melting point = 60-61°C.

IR (KBr): 3620cm-' (OH), l710 (C=O), 1430 (t-Bu), 1230 (P=O) and 1010 (P-0-C) MS: m/e = 630 (M”), 493 (M” HP OsEt z) NMR (CDC13) δ=6.89 (2s, each 2H), aromatic H3O9 and 5.03 (2s): OH4,1 (m, 4H): P-0-CH=CH535 and 3.25 (2m , 2H): Ph-CH2-CH-P3.04 (txd, LH): Ph-C Ht　CH(P)　C02,92,4(2m,4H):Ph-CH2CHt　C 01, 14 and 1.39 (2s, 18H each): t-CaHe1.32 ( t, J=7Hz, 6H):P　OCH2CHsH2O2 compound is diethyl 4-(3 ,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo-3-butyl tylphosphonate: 2.2 g (18% yield) of oil was obtained and on standing , it slowly solidified.

-Bu IRC liquid film): 3620cm-' (OH), 1710 (C=O), 1 430 (t-Bu), 1250 (P-0), 1010 (P-0-C) M S: m/e; 412 (M”), 274 (M HPOsEtz) NMR ( CDC13) δ=6.98 (s, 2H) aromatic H5, 1 (s, IH) ・OH 4, 14 (m, 4H): P OCH = CH53, 05 (d, J = 2 5Hz, 2H): CH, -P2, 94 (m, 2H): Ph-CH 2CH22,83 (m, 2H): Ph-CH, -CHtl, 42 (s, 18 H): t C+H*1.32 (t, J = 7H2, 6H): P-0-CH 2CHa Example 4 Diethyl 4-(3,5-not-tert-butyl-4-hydroxyphenyl)-1 , 1-7methyl-2-oxo-3-buten-1-ylphosphonate diethyl 1. 1-methyl-2-oxo-propylphosphonate (boiling point 60°C 102 mbar) V, Rouss and D.F. is and Tori, F., Wiemer), Journal on Organic Chemistry (J, Org, Chew, ) Dan 4. pp. 627-631 (19 Synthesized according to 89).

TiC14 (1,72 g-9 mmol), 3.5-not-tert-butyl-4-hydroxybenzaldehyde (0.9g.

38 mmol), diethyl 1,1-dimethyl-2-oxopropylphosphonate (1.0 g, 45 mmol), N-methylmorpholine (1.82 g, 18 mmol) ) was added continuously and the reaction mixture was stirred at room temperature for 1 hour. Perform post-processing using conventional methods. obtained an oil, which was subjected to column chromatography (SiOz, CHCl5/Ac0 It was purified by subjecting it to Et8/2). 11 g (yield 68%) of the title compound was obtained. melting point =91-92°C (petroleum ether 4O-60).

IR (KBr): 3440cm” (OH), 1670 (C=O), 1 590 (C=C), 1430 and 1410 (t-Bu), 1210 ( P=O) and 1030 (P-0-C) h4s: m/e=439 (M”+1), 259 (M’-C(CHs) 2 POsEtt), 57 (100%, r-Bu) NMR (CDCIs) δ=7.66 (d, J=16Hz, IH): Ph-CH=CH7,43(s, 2H) Aromatic H 7,26 (d, J=16Hz, IH): Ph-CH=CH5,55(s, IH )・OH 4,15 (m, 4H): P 0-CHi-CHsl, 50 (d, J = 17H z, 6H) Knee C (CH3) 2 Pl, 46 (s, 18H): t C aHe1.32 (t, J=7Hz, 6H): P-0-CH2-CHs elemental content Analysis: Calculated as Cz<Hs*OsP! [(%) C, 65, 73H, 8, 9 6P, 7.06 Measured value (%) C, 66, OOH, 8, 98P, 6.82 Example 5 Diethyl 4-(3,5-not-tert-butyl-4-hydroxyphenyl)-3 -Mechise Bu Diethyl 2-oxobutylphosphonate (boiling point = 60°C 10.2 mbar) , F. Mathey and P. Savinak ignac), Tetrahedron 34. 649 -654 page (1978).

TiCL (1,82g-9, 6 mmol), 3,5-di-tert-butyl-4-hydroxybenzaldehy (0.94 g 14 mmol), diethyl 2-oxobutylphosphonate (Ig , 4.8 mmol) and N-methylmorpholine (1.86 g, 18.4 mmol) ) was added continuously. The reaction mixture was stirred at room temperature for 30 minutes, then heated for 1 hour. It refluxed. After normal work-up and extraction, the crude reaction mixture was subjected to column chromatography. Precise by graphics (Sift, CHCis/AcOEt8/2) Manufactured. First, a small amount of unreacted henzaldehyde is collected, and then 0.0% of the title compound is collected. 35g (21%) was obtained. Melting point = 97-101°C (petroleum ether 4O-60).

IR (KBr): 3400cm-I (OH), 1680 (C=O), 16 10 and 1590 (C=C), 1440 (t-Bu), 1250 ( P=O) and 1020 (P-0-C) MS + m/e = 424 (M, 409 (M”-CH5), 367 (M ・-tBu), 286 (M”-HPOsEti), 57 (100%, tBu Two NMR (CDC1s) δ−7,63t 7,33 (s, 2H) aromatic H 5,,) (S, LH):OH 4,16 (m, 4H): p 0-CHx CHt3, 51 (d, J = 22 Hz, 2H): CH, -P2, 1 (s, 3H): CH3 1, 46 (s = 18H): t CaHe1.32 (t, J = 7Hz, 6 H):P　OCHz　CHs elemental analysis/as C2*HstOsP Calculated value (%) C, 65,07H, 8,79P, 7.30 measurement fil (%) C ,65,35H,8,58P,7.51methyl 4-(3,5-tert- Butyl-4-hydroxyphenyl)-3-(n-butyl)-2-oxo-3-butyl ten-1-ylphosphonate 3,5-di-tert-butyl-4-hydroxybenzene Nuzaldehyde (3.65 g, 15 mmol), dimethyl 2-oxoheptyl Phosphonate (4.0 g, 18 mmol), TiC1> (6.84 g-36 mmol) and N-methylmorpholine (7°27 g, 72 mmol) in dry T A warm mixture of HF (80 ml) was refluxed as described in Example 7. column chroma Subjected to tography (SiOt, CHC13/ACOEt 8/2) Purification was performed to obtain 1.2 g (yield 20%) of the title compound. Melting point +82-85℃ (petroleum ether 4O-60).

MS + m/e = 439 (M゛+1), 438 (M two, 381 (M"-C 4H*), 57 (100%, tBu) NMR (CDC1s) δ-7,63 (s, LH) ・Ph-CH=C (C, He) 7.32 (s, 2 H): Aromatic H 5,5(s, IH):OH 3,81 (d, J=11Hz, 6H): P-0-CHt3,52 (d, J =22Hz, 2H): CHz-P2.57 (m, 2H): CHi-C 3H.

1.5 1.4 (m, 4H): CHt (CH2)2 CH31,5 (s, 18H) ・t-C4H・0.94 (t, J=7Hz, 3H) + (CHi) i CHs Example 7 Diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2 -oxo-3-phenyl-3-buten-1-ylphosphonate phosphonate reagent as diethyl 2-oxo-3-phenylpropylphosphonate (boiling point = 15 The method described in Example 5 was used. Normal article For column chromatography (SiCh, CHCb/Ac0Et 8/2) The title compound was isolated in approximately 18% yield. Melting point = 139-143°C.

IR (KBr): 3500cm-' (OH), 1640 (C=O), 1 610 and 1590 (CC), 1430 (t-Bu), 1230 (P=O) and 1020 (P-0-C) MS: m/e=486 (100%, M”), 348 (M”-HPO, E tz), 335 (M”CH2PO3Eh) NMR (CDC13) δ-7,63 (s, LH): Ph-CH=C7,45-7,25 (m, 5H) :C5Hs6.97 (s, 2H) aromatic H 5,46(s,LH):OH 4, 15 (m, 4H): P OCH2-CH53, 33 (d, J = 2 2Hz, 2H): CH2Pl, 32 (t, J = 7H2, 6H): P 0-CHz-CH31, 23 (s, 18H): C4H* Elemental analysis: C As zsHuOsP Calculated value (%) C, 69, 11H, 8, 08P, 6.37 Measured value (%) C, 69 , 37H, 8, 11P, 6.61 Example 8 /ethyl 4-(3,5-not-tert-butyl-4-hydroxyphenyl)-1 -Methyl-2-oxo-3-buten-1-ylphosphonate Same as described in Example 5 Similarly to the method of Mathey and Savignac. Therefore, diethyl 1-methyl-2-oxopropylphosphonate was prepared.

3.5-tert-butyl-4-hydroxybenzaldehyde (7.19g , 29 mmol), diethyl 1-methyl-2-oxopropylphosphonate (8 , 20 g, 35 mmol), Ticl, (13,47 g - 71 mmol), N - Methylmorpholine (14.34 g, 140 mmol) in dry THF (150 ml) The warm mixture was allowed to react for 1 hour at room temperature and then for 18 hours at reflux temperature. Post-processing After that, column chromatography (SiCh, CHCl3/Ac0Et 8/2) 4.7 g (38%) of the title compound was obtained.

Melting point = 92-94°C.

NMR (CDC13) δ-7,63 (dj=16Hz, IH): Ph-CH=CH7,42 (s, 2 H) Aromatic H 6,87 (d, J=16Hz, IH): Ph-CH=CH5,6 (s, IH) :OH 4.15 (m, 4H): P-0-CH, -CH5353 and 3.46 (2 -) d, J = 24 Hz and 7 Hz, LH): CH-P 1.50-1.43 (2=+d, J=7Hz): CH(P) CHsl, 4 6 (s, 18H): CsH*1.32 (2 t, J=7Hz): PO C82CH3 Example 9 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2 -oxo-3-buten-1-ylphosphonate dimethylene at -60°C under nitrogen atmosphere of n-butyl phosphonate (3.17 g, 25°6 mmol) (16M solution in hexane, 1.6 ml, 256 mmol) in anhydrous HF (1 5 ml) of the solution. The reaction mixture was stirred at -50°C for 30 min and the lithium Fully formed anion (slightly opaque deafness). The mixture was brought back to -60°C. Cool and add ethyl 3.5-di-tert-butyl-4-hydroxynon-1- A solution of (2.6 g, 8.5 mmol) in dry THF was added. The resulting orange mixture The mixture was stirred at room temperature (25°C) for 18 hours. Add 10ml of 10% HCI solution Hydrolysis was carried out by evaporating the ether to give a yellow solid. 40- Recrystallized with 60 petroleum ether to give dimethyl 4-(3,5-not-tert-butyl -4-hydroxyphenyl)-2-oxo-3-buten-1=ylphosphonate (3.0 g, yield 92%) was obtained.

Melting medium = 107-109°C.

Mat:, the title compound contains n-BuLi and LDA (lithium salt) as bases. sobropyramide). n-butyl Lithium (16M solution, 16 mL 25.6 mmol) in dry THF (20 m Isoprobylamine (0.86 g, 8.5 mmol) was added to the solution in l) at -60°C. ) was added. The resulting mixture was stirred at -40°C for 15 minutes and then diluted with phosphonate (2.11 g, 17 mmol) was added. After 15 minutes, ethyl 3. 5-di-tert-butyl-4-hydroxyannamate (2.6 g, 8.5 mmol) was added and the reaction mixture was stirred at room temperature (25° C.) for 15 hours. 10% After work-up by addition of HCI and extraction with ether, dimethyl 4-(3, 5-di-tert-butyl-4-hydroquinophenyl)-2-oxo-3-bute Obtained 3.10 g (95%) of ion-1-ylphosphonate.

Melt = 107-IC19°C.

Compounds produced by either of these two methods can be used as described in Example 1. It has the same data as the spectroscopic data of the composition.

Elemental analysis, as C2°H,, O, P Calculated value (%) C, 62, 81H, 8, 17P, 8.10 Measured value (%) C, 6 2,56H,8,21P,8.24 Example 10 Diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-1 ,1-methyl-2-oxo-3,5-hexanoen-1-ylphosphonate 0 TiCL (1.23 g, 6 ．． 47 mmol L3.5-tert-butyl-4-hydroxyneamal Dehyde (07 g, 2 mmol), diethyl 1,1-dimethyl-2-oxo Propyl phosphonate (0.72 g, 324 mmol) and N-methylmorpho Phosphorus (1.31 g, 12.97 mmol) was added. The reaction mixture was heated at 20°C for 1 hour. The mixture was then stirred at 30° C. for 1 hour. After treatment, a dark oil was obtained, which was applied to the column. Chromatography (Si02, CHCh/Ac0Et 8/2) I:, J-1 Manufactured by 1JI. Yellow crystals (650 mg, 52%) were obtained. Melting point = 130-133 ℃.

NMR (CDC13) δ=7.40 (dxd, J=11 and 15Hz, 1) ().

Ph-CH=CH-CH=CH 7,2(s,2H) aromatic H 687 and 6.85 (2d, J=15Hz, 2H): Ph-CH=CH-C H=CH 6,75 (dxd, J=15 and 15Hz, IH) Ph-CH=CH-CH= CH 5, 4 (s, LH): OH 4,1 (m, 4H): P-0-CHz CH31, 40 (d, J = 16 Hz, 6H): C(CHri! 1.39 (s, 18H): t-C4H.

1.24 (tj=7Hz, 6H): P-0-CH2-CH3\Is: m/e =464 (M-), 326 (M"-HPO, Eh), 285 (100% , M’　CMe2　P　Os　E　t2) Elemental analysis C2, H, ○, P hand Total X @ (%) C, 67, 22H, 8, 90P, 6.67δ creeping fixed value (%) C, 66, 68H, 8, 56P, 6.21 Example 1■ Dimethyl 4-(3,5-di-Lcrt-butyl-11-hydroxyphenyl)- Dimethylmethylphosphonate (3.2 g, 25.6 n-butyllithium (16 ml of 16 M solution in hexane, 256 mmol) mol) in dry THF (15 ml). A methylphosphonate solution was prepared. To this solution, at -60°C, add ethyl 3.5- Di-tert-butyl-4-hydroxyhydrononamate (2.6 g, 8 ．． A solution of 5 mmol) in THF (20 ml) was added. 160% of the obtained solution C. for 30 minutes and then brought to room temperature (25.degree. C.) overnight. 10%H CI (25ml) was added and the mixture was extracted into ether. ether phase residue Column chromatography (SiO2, CHCh/Ac0Et 8/2) I: Purification was carried out to obtain a white solid. Recrystallization in petroleum ether gave the title compound ( 2.1 g, yield 64%) was obtained.

Melting point = 78-79°C.

MS: m/e=384 (M'), 284 (M'''-HPOsMez), 57 (100%, tBu=) NMR (CDC13) δ=6.98 (s, 2H): aromatic hydrogen 5.06 (s, IH): OH 3,75 (d, J=11.5Hz, 6H): P-0-CHz3.08 (d, J=22.3Hz, 2H): CHz P2.90 (m, 2H): Ph-CH tc)I.

2.81 (m, 2H): Ph-CHz-CHzl, 41 (s, 18H): t-C-Henoekyl 6-(3,5-not-tert-butyl-4-hydroxy phenyl)-2,4-7oxo-5-hexen-1-ylphosphonate-Bu Diethyl 2-oxopropylphosphonate (3.4 g, 17 mmol) was added to nitrogen Dry sodium hydride (0.82 g of 60% dispersion, 20 mmol) at room temperature under Added to suspension in THF (35ml). The mixture was stirred at room temperature for 60 minutes and then Addition of isopropylamine (1.71 g, 17 mmol) at 0°C followed by Add n-butyllithium (21 mL of a 16M solution in hexane, 34 mmol). Ta. After 30 minutes at 0°C, the mixture was cooled to -60°C and diluted with ethyl 3,5-di -tert-butyl-4-hydroxy nonnamate (2.6 g, 8.5 mm A solution of THF (25 mL) was poured into the solution. The resulting mixture was heated at 0°C for 2 hours. , stirred for 1 h at 25°C, hydrolyzed with H2O (60 mm), then the mixture was separated into two phases. The aqueous phase was acidified with 10% HCI and added with 100 ml of 1 part ether. Extracted twice.

The ether extracts were pooled with the THF phase, dried and evaporated. Color the cruelty Purified by microchromatography (Sigh, CHCb/Ac0Et 8/2). A viscous orange oil was obtained. Recrystallized in ligroin to obtain the title compound (2.25 g, A yield of 60% was obtained.

Melting point = 109-110°C.

NMR (CDC1x) δ=7.60 (d, J=16Hz, IH): Ph-CH=CH7,37(s , 2H) Aromatic hydrogen 6.35 (d, J=16Hz, IH): Ph-CH=CH5,83(s, I H): C0-CH=C-0H5,54 (s, IH) near z nor OH4,17 ( m, 4H): P 0-CH*CHs3.02 (d, J=22Hz, 2H): CH* Pl, 46 (s, 18H): t C4He1.34 (t, J=7Hz, 3H): P0-CH2CHsMS: m/e=452 (M” ), 314 (M”-HPOsEt*), 57 (100%, tBu) Example 13 Diethyl 6-(3,5-tert-butyl-4-hydroxyphenyl)-2 ,4-diethyl 2-oxobrobylphosphonate (2.02 g, 10 mmol) of sodium hydride (60%) suspended in THF (30ml) at room temperature. (048 g, 12 mmol) of the dispersion. After 30 minutes, cool the mixture to 0°C and noisopropylamine (1°Olg, 10mmol) and n-butyllithium (1.21 mmol of 13 ml of 16M solution) was added. After 30 minutes, the mixture Ethyl 3.5-ditert cooled to 60°C and dissolved in THF (15ml) -butyl-4-hydroxyhydro/namate (1.6 g, 5.2 mmol) Added.

The mixture was reacted at -60°C for 15 minutes, then at 0°C for 2 hours, and at 25°C for 1 hour. , hydrolyzed with 10% HCI and extracted with ether. column chromatography (Sin,, CHC1z/Ac0Et 8/2), the title compound was obtained as a colorless oil. (10 g, 42%) was obtained.

N M R (CD Cl s) δ=6.98 (m, 2H) Aromatic hydrogen 5.70 (s, IH): Co-C H=C-0H5,09 (s, IH) Phenol OH4,15 (m, 4H):P OCH2CH32,92 (d, J=22.5Hz, 2H) +CH, -P2.8 5 (m, 2H): Ph CH2CH2259 (m, 2H): Ph CH2 CH21,,43(s,18H)+tC4H11,33(t,J=7Hz, 6H): P-OCH2CHsMS: 4. )O(M’+1), 454( M”), 436 (M-HzO), 57 (100%, tBu) Example 14 2-methyl 6-(3,5-tert-butyl-4-hydroxyphenyl)-2 ,4-nooxo-5-hexen-1-ylphosphonate -Bu The procedure described in Example 12 was performed using 2-methyl 2-oxopropylphosphonate. The title compound was obtained as a yellow solid with a melt temperature (145-146°C) (yield 79%). ) was obtained.

Example 15 2-E4-(3,5-not-tert-butyl-4-hydroxyphenyl)-2- Oxo-3-buten-1-ylco(2-year-old xo-1.3.2-nooxaphosphorus) 2-methyl dissolved in THF/nooxane (30 ml each) under nitrogen atmosphere -2-oxo-1,3,2-nooxaphosphorinane (2.62g, 19.2ml) n-butyllithium in an equimolar amount in THF (35 mmol) at -60°C. added to the program.

The mixture was stirred at -60°C for 30 minutes and then diluted with ethyl 3.5-di-tert-butyl alcohol. Thiru-4-hydroxy nonnamate (2 g, 6.4 mmol) in THF (20 milli) was added to the solution. The resulting mixture was stirred at -60°C for 30 minutes and then for 16 hours. Room temperature (25°C) was reached over time. After normal post-treatment, column chromatography The title compound was determined by matoography (Nori Riki Gel, CHCl5/MeOH98/2). (0.76 g, 30%) was obtained.

Melting point = 158-161°C.

MS: m/e = 394 (M'), 57 (100%, tBu) NMR (C DCIs) δ=7.65 (d, J=16Hz, IH): Ph-CH=CH7,42(s , 2H) Aromatic hydrogen 6.74 (d, J=16Hz, LH): Ph-CH=CH5,7 (s, IH) :OH 4,5-4,4 (large m, 2H): P-〇-CH.

3.4b (d, J=22Hz): CH2-P21 and 2.0 (2m, 2H ):p OCH2CH21,45(s, 18H):t-C,H.

Example 16 /ethyl 4-(3,5-not-tert-butyl-4-hydroxy)-4-oxo -2-60% sodium hydride (730 mg, 18 mmol) in THF (20 ml)-4-hydroxyphenyl)-2-oxo-1-ethylphosphonate (3 ,0g.

84 mmol) was added. The mixture was stirred for 30 minutes, then cooled to 0°C and Tylformyl methylphosphonate (3.1 g, 18 mmol) was added. obtained The mixture was stirred at 0°C for 1 hour, then at 25°C for 16 hours, and then mixed between ether and water. Partitioned and the organic phase was evaporated. Column chromatography (silica gel, dichloromethane) purification with romethane/methyl t-butyl ether 98/2) to give the title compound (5 50 mg, 16%) was obtained.

Melt, fortune = 68-70°C0 MS=m/e: 410 (M”), 395 (M-CH3), 272 ( M’-HPO3Et2), 233 (100%, M”-CH=CHCHzPO sEh) NMR (CDC13) δ=7.83 (m, 2H) Aromatic hydrogen 7.10 (dd, J=15 and 4 ．． 5Hz, IH): Ph-Co-CH=CH6,9(m, 2H): Ph-Co -CH=CH5,7 (s, IH): OH 4,15 (m, 4H): P OCHz CHz2.86 (dd, J=23 and 7Hz): CH2Pl, 48 (s, 18H): t-CtHel, 34 (t, 6H): P-0-CHz-CI-130ki/-3-buten-1-ylpho Suphonate - trimethyl 4-(3,5-di-tert-butyl) cooled to 10°C 4-hydroxyphenyl)-2-oxo-3-buten-1-ylphosphonate ( 1.9 g, 5 mmol) in methanol solution (100 ml) of sodium borohydride. Lium (0°75g) was added. The reaction mixture was heated to -10°C for 1 hour, then to room temperature. The mixture was stirred at (25°C) for 2 hours. Ether (100ml) and sodium bicarbonate Post-treatment was carried out by adding a solution of 60 ml of silica. ether phase with salt water Washed, dried over Mg5O1 and evaporated to give the title compound (1.6g, 85%). Ta.

Melting point = 122-123°C.

MS (m/e) = 384 (M"), 366 (M" H2O), 256 (M” H2O-HP OsMez) NMR (CDCI, ) δ=7.21 (s, 2H): aromatic hydrogen 6.59 (d, J=16Hz, L H): Ph-CH=CH6,08 (dd, J=16 and 6Hz, IH):P h-CH=CH5,26 (s, LH): OH (phenol)4,7 (m, I H): CH-OH3,78 (2xd, 6H): PO1Me234 (hump-shaped , IH):CH-OH 2,15 (curved d, 2Hz): CH2Pl, 44 (t, 18H ): t-C,Hs-methyl 4-(3,5-not-tert-butyl-4-hydro xyphenyl)-2-oxy under nitrogen atmosphere, trimethylmethylthionophosphonate ( 3.1 g, 25 mmol) was added to n-butyllithium (1.6M solution) at -60°C. 16ml) of THF (50ml) at medium temperature. The mixture was heated to -60°C for 15 minutes. Stir for a while, then add ethyl 3.5-7-tert-butyl-4-hydroxy nonna A warm solution of Mate (2.5 g, 8.2 mmol) in THF (20 ml) was added.

The resulting mixture was stirred at -60°C for 30 minutes and at room temperature (25°C) for 2 hours. usually After hydrolysis and work-up, the compound was subjected to column chromatography (S iCh, CHCl5/Ac0Et 9/1) and CHCl! /in petroleum ether The product was purified by recrystallization to obtain a yellow solid (1.7 g, 152%). Melting point = 88- 90℃.

MS: m/e=398 (M”), 259 (M’-CHtP(SXOMe )z), 125 (P(S)(OMe)2), 57 (100%) N M R (CD C13) δ=7.60 (d, J=16Hz, LH): Ph-CH=CH7,42 (s, 2H) Aromatic hydrogen 6.75 (d, J=16Hz, IH): Ph-CH=CH5,6(s, IH ) :OH 3,78 (d, J-14Hz, 6H): P(S)-〇CHI3.56 (dl= 20Hz, 2H): CH2Pl, 46 (s, 18H): t C4HeCr a　Hs　(Ot　PS　Calculated value (%) as C, 60, 28H, 7, 84 P, 7.77 S, 8.04 Bari fixed fil (9fi) C, 60, 58H, 8 ,04P,8.05S,8.30-60°C Ethyl 3.5-not-tert- T of butyl-4-hydroxyphenylthioacetate (2 g, 6.2 mmol) A medium temperature solution of HF (15 ml) was added.

The resulting mixture was stirred at -60°C for 30 minutes and then heated to room temperature (25°C) for 4 hours. I tried to reach . After addition of 10% Hct (15 ml), the reaction mixture was evaporated with ether. and water. After evaporating the organic phase, the residue 1 was subjected to column chromatography. - (S102, CHCl5/Ac0Et 8/2) and recrystallization (petroleum ether ) to obtain the title compound (0.95 g, 38%).

Melting point = 63-65°C MS: m/e 402 (M, 251 (M' CH2-P03MeJ, 57SMR (CDC13) δ=7.21 (s, 2H): aromatic hydrogen 5.3 (s, LH) OH 3,75 (dj=11Hz, 6H): P-0-CHz3.72 (s, 2H) ・S-CH2-CO3,33 (d, J=22Hz, 2H): CHz Pl, 41 (t, 18H)+t-C+Hs Example 20 -Ninomethyllithiomethylposponate (68.2 mmol) kept at 60°C Ethyl 2-(3,5-di-tert-butyl-4) was added to a THF (10 ml) solution of -Hydroxyphenyl-thio-2-methylpropionate (6g, 17.1ml Mol) stir and chamber for 4 hours! (25°C). 10%HC After addition of I (15ml), the reaction mixture was partitioned between ether and water. organic phase The residue after evaporation was subjected to column chromatography (Sin, CHC1a/A c0Et 8/2). Recrystallized from petroleum ether to obtain the title compound. (4.16g.

57%).

Melting point = 105-106℃ MS: m/e 430 (M”), 279 (M”) (Co CH2POs Mez)), 197 (100%), 57 NNIR(CDCl2) 6=7.15 (s, 2H) aromatic hydrogen 5.38 (s, IH): OH 3,80 (d, J = 11Hz, 6H): P OCHI3, 46 (d, J =22Hz, 2H): CH2-Pl, 41 (t, 24H): t - C, HI+C(CH3)2 Example 21 /methyl 4-(3,5-di-tert-butyl-4-vitroquinophenyl)-1 ,3-butanoen-1-ylphosphonate 7 methyl 4 (3,5-7-tert-butyl-4-hydroxyphenyl)-2 -Free of hydroxy-3-buten-1-ylphosphonate (23 g, 6 mmol) A warm mixture of acetic acid (1,70ml) and triethylamine (1,26ml) was added to The mixture was stirred at 0°C for 3 hours. After hydrolysis with H2O (10 ml), the reaction mixture was diluted with Extracted with ethyl ether (20ml). The ether phase was extracted with 10% HCI, Dry over N.IgSO1. The residue 1 after evaporation was subjected to column chromatography. and refine it, ff! A combination compound (1.0 g, 46%) was obtained.

Melting point, = 113-115°C.

MS: m/e: 366 (M”), 351 (M’-Me), 57 (tBu)NMR (CDC13) δ=7.32-7.20 (m, 3H): aromatic hydrogen + CH=CH-CH=C H-P6.82 (IH, d) knee CH=CH-CH=CH-P6.74-6. 66 (IH, d): CH=CH-CH=CH-P5.67 (LH, dd, J = 16.6 and 19.5Hz) CH=CH-CH=CH-P 3 75 (d, 6H): POCH3 1,46(19H,s): t-C4Ht Example 22 /methyl 4-(3,5-not-tert-butyl-4-hydroxyphenyl)-2 -(4-pentenoyloxy)-1-butylphosphonate acetyl-4-pente Noate (0.66 g, 4.6 mmol) and triethylamino (0.24 m 1.7 mmol) of dimethyl 4-(3,5-7-tert-butylene). -4-hydroxyphenyl)-2-hydroxy-1-butylphosphonate (0 50 g, 137 mmol) were added. The reaction mixture was kept at 60°C for 6 hours. Hold, cool, and extract into diethyl ether and water. Residual weight of dried organic phase Column chromatography (SiO2, CHCl3/methyl-tert- Butyl ether) to give a colorless oil (04 g, 62%).

MS: m/e: 468 (M-), 368 (M”-CH2=CHCH 2C00H), 258 (368-HP○3Mez) NNIR (CDC13) δ=6.94 (s, 2H) Aromatic hydrogen 5.85 (m, LH) lcH2=c HCH2CH2C00H5,18 (m, IH):ph CH2CHI-CHCH 2P5.0 5.1 (m, 2H): CH2=CH-CH2CH2Co.

0.15 (s, IH): OH (phenol) 3.72 (2xd, 6H): P○1Me22.55 (m, 2H): Ph-CH2CH2-CH-CH2 P2.41 (m, 4H): CH1=CHCH2CH2Co.

1.43 (s, 18H): t-C4He Table 1 Phosphonate of formula (1) The table shows the biological activity of the phosphonate (continued) of formula (1). 1) Iron-induced peroxide formation in rat liver homonates by ether inhalation Wistar rats were euthanized. Dissect the liver and add 4 times the volume of phosphate buffer. (4°C, pH 7.4) using a Porter homogenizer. 20 After centrifugation at 0 rpm for 10 minutes, the resulting supernatant was kept at 4°C.

A mixture containing liver homomonate (0.2 ml) and phosphoric acid 11i solution (1.7 ml) was added. Incubate with 2 mM FeS O4 solution (0.1 ml), By A. T. Quintanilha et al. Ann, N. , Y, Acad, Sci,) 393. 32 47° 1982 Peroxide formation was induced according to the method described.

The compound to be tested for antioxidant activity was dissolved in DMSO or ethanol and A volume of μm was added to the incubation mixture. Step by step extract stock solutions of compounds. Subsequent dilutions were made to obtain final concentrations of 05.1.2.5 and 5 μM. Oxidation at 37℃ for 2 hours and stopped by adding 2% BHT ethanolic solution (20 μm). I set it. The peroxide formed, measured as malondialdehyde formation, was Using birlic acid reaction and using 1.1.3.3-tetramethoxypropane as a control. The Yagi method (``Lipid peroxides in biology and medicine J22 pp. 3-242, Kay Yagi (Ed.), Academic Press. ・Incorporated (＾cademic Press Inc, )) Therefore, it was quantified. μmol results in inhibiting malondialdehyde formation by up to 50% /I concentration.

All test compounds had IC50's between 05 and 5 μM, with probucol (Pro bucol), more active than vitamin E and vitamin C. butylhydro Xytoluene (BHT) has an IC50 of 3.3 μM in the assay. Thus , compounds of formula (I) are useful in the treatment of conditions involving oxygen-reactive species.

Inhibition of iron-induced rat liver homogenate oxidation Probucol >25 18 3.56 Vitamin E > 25 19 2.49 Vitamins (>25 9 4.18 BHT 3.3 12 1.71 1 2.01 10 3.48 2 3.20 14 3.07 3 1.37 20 2.44 4 1.41 24 4.55 15 1.50 25 2.71 16 4.89 26 0.68 17 3.03 27 0.70 11 2.85 28 1.0 13 1.88 32 2.78 5 3.18 33 5.0 6 2.38 34 2.91 7 2.06 35 2.84 2) Copper oxidation of human low-density lipoprotein (LDL) donor blood was subjected to low-speed centrifugation. plasma was obtained. LDL (d=1.006-1, 063 g/ml) in salt solution Isolated by preparative ultrafiltration in liquids (NaBr, KBr). Isolated LDL Rakucon was dialyzed against phosphate buffer.

LDL oxidation was described by Esterbauer et al. Continuous monitoring of proteins in vitro, free rad response research Mun (Continuous Monitoring of in Vitro Oxidation of Hu++ an Low Dens Amakashi■ Lipoprotein, Free Rad, Res, Common, ), 67-75, 1989). Simply, LDL suspension (50-200 μg protein/ml) was divided into quartz cuvettes and kept at 37°C. , then CuCl2 solution was added at a final concentration of 5 μM. U ■ - Visible spectrograph The increase in optical density at 235 nm was recorded using a photometer. Oxidation takes time The temperature was recorded at 10 minute intervals over a period of 8 hours. Compound to be tested in ethanol Dissolved and added at a final concentration of 0.1 μM. Controls received ethanol only. logarithm The period is extended by the presence of antioxidants. This method was used to test probes as reference antioxidants. Confirmed with kohl and vitamin E.

The prolongation of the logarithmic phase is used to quantify the antioxidant activity of the test compound, and this prolongation is Measured in the absence of an antioxidant (control) Expressed as a percentage of the value.

The phosphonates of formula (1) listed in Table 3 prolong the log phase compared to the control.

The inhibitory activity on LDL oxidation was measured, and the activity was compared with probucol and vitamin It is clearly superior to the inhibitory activity of In-E. These two antioxidants were tested on animals. Formula (1) has been shown to have anti-atherosclerotic activity. The therapeutic potential of phosphonates is clear.

Inhibition of copper-induced LDL oxidation Compound Logarithmic phase (control %) Compound Logarithmic phase (control %) 15 + 233 24 +16 16 + 159 25 + 118 13 +191 28 +48 18 + 223 35 + 118 B Inhibition of cholesterol and cholesteryl ester synthesis Human intestinal cell line CaC The formula for cholesterol synthesis ([ ) studied the effects of compounds. The cells were grown in 6-well dishes (Falcon) for 2 Dulbecco's modification of 0% calf serum (Flow) supplementation It was grown in Eagle's medium (2 ml). Cells, 5% co! Under atmosphere, 37℃ Labeling experiments were performed for 8 days after cell culture. Add test compound to the culture medium. 10 μm of tanol solution was added. Control wells received 10 μl of ethanol alone. T-ko. After 1 hour, Q, 7 μCi of 14-C-acetate (53,4 mC1/milli mol), continue yATR conversion for 4 hours, and wash the cell layer with cold PBS. The tsm operation was stopped. cells to 0. OIN NaOH (2ml) and PB Collected in S (1 ml). Lipids were extracted by Folch method and petroleum ether .

Norikagel TLC developed with diethyl ethyl: vinegar (70:30/0.5) Separated on a plate. After exposure to iodine gas, cholesterol and Scrape off the band corresponding to the steryl ester and apply liquid scintillation soda. Radioactivity was measured in a counter.

In the presence of test compounds, cholesterol and cholesteryl esters are incorporated into The amount of radioactivity obtained was compared with that in control cells. HM like simpastatin GCoA reductase inhibitor (1 gM) This was used to confirm the incorporation value of 14(-acetate in Stell).

All test compounds inhibited cholesterol and cholesteryl ester synthesis. (Table 4). The phosphonate of formula (1) contains cholesterol and cholesteryl esters. Shows inhibitory activity on esters and is used in the treatment of hyperlipidemia and atherosclerosis. It is considered to be a therapeutic agent for the treatment of cancer.

Cholesterol, a compound that inhibits cholesterol and cholesteryl ester synthesis Calcium entry blocking activity experiment of cholesteryl ester C ketophosphonate, Male Sprague Dawley rats killed by stunning and exsanguination (weight 280-350 g). Remove connecting tissue from thoracic artery , cut into tubes approximately 2 mm long. The container was fixed under a static tension of 2 g and the 95% 02 ．． HEPES buffered Ringet solution (buffer Composition (mM): NaC1139,05KC15,01MgC113,7, D-g 10ml of braided fiber containing Lucose 110, HEPES 5.0, pH 7.4) Equilibration was carried out for 1 hour at 37°C in a bath.

Maximal contractions were obtained within 5-10 minutes of exposure to 10 μM phenylephrine.

The tissue was then washed with HEPES buffer (a)2-free. After 30 minutes, the tissue was Depolarized with KCI (60mM). 100 μl vehicle (10% DMSO) or or a solution of the compound (1 gM) was added after 5 minutes. The final degree of DMSO is 1%. It was. Tissues (n = 2/compound ) was further equilibrated for 15 minutes in the presence of compound. for each concentration of calcium Contractions were calculated as a percentage of another phenylephrine contraction, EC. (Phenylephrine Jrx) of Ca″2 resulting in 30% contraction of Expressed as concentration ratio (Cal/Ram Drug E Cs./Vehicle EC36). Efficacy index> 1 indicates that the compound is effective.

Therefore, the compound of formula (1), through its calcium entry blocking activity, It is useful in the treatment of tube diseases. The primary indication for these compounds is atherosclerosis. Treatment of sclerosis, angina, congestive heart failure and hypertension.

Effect of compound (+) on Ca”-induced contraction of arteries of polarized rats Compound EC,. ratio Continuation of front page (81) Specified times EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN.

TD, TG), AT, AU, BB, BG, BR, BY.

CA, CH, CN, CZ, DE, DK, ES, FI, GB, GE, HU, JP, KG, KP, KR, KZ, LK, LU, LV, MD, MG, MN, MW, NL, No.

NZ, PL, PT, RO, RU, SD, SE, SK, TJ, UA, US, UZ, VN (72) Inventor: Flore, Simon Belsonne 01210, Route de d'Iponne, Country of Frares (no street address displayed) (72) Inventor: Azoulay, Remore No. 11, Rue de Gaulle, 1260 Nion, Switzerland (72) Inventor: Guyon-Guerin, Building, 74100 Annemas, Yvefrares - Raglan, Rue des Cailles 3rd place (72) Inventor: Maescherer, Vinyl Switzerland Plan-Raise-Wate 1228 , Chemin Pré du Cain No. 12 (72) Inventor Niezor, Ericsson, Switzerland 1260, Chemin de ・Ponmon, 13th Se Ichiban (72) Inventor: Benzen, Flave Elswiss Posybossy 1261 , Chemin de Chevrerie No. 3

Claims (15)

[Claims] 1. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, -X1, X2 are the same or different, straight chain or branched C1-C6 alkyl groups and -Y is O or S; -Z1 and Z2 are the same or different, -OR (wherein R is H, linear or branched); branched C1-C6 alkyl group), -NR1R2 (herein, R1 and R2 are the same or is different from H or a straight-chain or branched C1-C6 alkyl group, -Z1 and Z2 together form a C2-C8 alkylidenedioxy group Good too, -G is OH or its bioprogenitor group and -D is saturated or unsaturated C1-C11 It is an alkylene chain, of which one or more methylene groups are sulfur atoms, oxygen atoms, carbonyl groups, optionally one or more The tyrene group has one or more halogen atoms (F, C1 or Br), C1-6 even if substituted by alkyl, phenyl, hydroxy or acyloxy groups good] A compound represented by or a salt, solvate or hydrate thereof. 2. D is A-C(O)-B, A-CH(OH)-B, A-CH2-B, (CH2 )t-(CH=CH)n-(CH2)t or S-(CH2)t, where -A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CHX 3, S-(CH2)t-(CH=CH)n, S-CX4X5, (CH=CH)n -CH=CH-C(O)-CHX3, (CH2)p-CH=CH-C(O)-C HX3, (CHX)t-C(O)-CHX3, S-(CH2)t-(CH=CH )n-C(O)-CHX3, S-CX4X5-C(O)-CHX3, (CH=C H) n-CH=CH-CH(OH)-CHX3, (CH2)P-CH=CH-C H(OH)-CHX3, (CH2)t-CH(OH)-CHX3, S-(CH2 )t-(CH=CH)n-CH(OH)-CHX3,S-CX4X5-CH(O H)-CHX3, where n is 0, 1 or 2, and t is a number from 0 to 4. and p is a number from 1 to 3; -X3 is H, linear or branched C1-C6 alkyl group, substituted or unsubstituted phenyl group is a group, -X4, X5 are the same or different, H, linear or branched C1-C4 alkyl is the basis, -B is CH2, CH-X6, X6-C-X7 (here, X6 and X7 are the same or different, halogen atoms (F, C1, Br), linear or branched C1-C6 alkyl group, substituted or unsubstituted phenyl group); A is (CH2)t, (CH =CH)n-CH=CX3, (CH2)t-CHX3, S-(CH2)t-(C If H=CH)n, S-CX4X5, B is also CH=CH-(CH2)p , CH=CH-CHX6, CH=CH-CX6X7, where p and X6, The compound of formula (I) according to claim 1, wherein 7 is as defined above. 3. D is A-C(O)-B, where -A is (CH2)t, (CH=CH) n-CH=CX3, (CH2)t-CHX3, S-(CH2)t-(CH=CH )n, S-CX4X5, (CH=CH)n-CH=CH-C(O)-CHX3, (CH2)p-CH=CH-C(O)-CHX3, (CH2)t-C(O)-C HX3, S-(CH2)t-(CH=CH)n-C(O)-CHX3, S-CX 4X5-C(O)-CHX3, (CH=CH)n-CH=CH-CH(OH)- CHX3, (CH2)p-CH=CH-CH(OH)-CHX3, (CH2)t -CH(OH)-CHX3, S-(CH2)t-(CH=CH)n-CH(OH )-CHX3, S-CX4X5-CH(OH)-CHX3, where n is 0, 1 or 2, t is a number from 0 to 4, and p is a number from 1 to 3; -X3 is H, linear or branched C1-C6 alkyl group, substituted or unsubstituted phenyl group is a group, -X4, X5 are the same or different, H, linear or branched C1-C4 alkyl is the basis, -B is CH2, CH-X6, X6-C-X7 (here, X6 and X7 are the same or different, halogen atoms (F, C1, Br), linear or branched C1-C6 alkyl group, substituted or unsubstituted phenyl group); A is (CH2)t, (CH =CH)n-CH=CH3, (CH2)t-CHX3, S-(CH2)t-(C If H=CH)n, S-CX4X5, B is also CH=CH-(CH2)p , CH=CH-CHX6, CH=CH-CX6X7, where p and X6, The compound of formula (I) according to claim 1, wherein 7 is as defined above. 4. D or -ACH(OH)-B, where A and B are the same as in claim 2. A compound of formula (I) according to claim 1, which is the same. 5. D is A'-CH(O-CO-X■)-B', where A' is (CH2) t, (CH=CH)n-CH=CX3, (CH2)t-CHX3, S-(CH2 )t-(CH=CH)n, S-CX4X5, and B' is CH2, CH-X6, X 6-C-X7, CH=CH-(CH2)p, CH=CH-CHX6, CH=CH -CX6X7, and t, n, p, X3, X4, X5, X6 and X7 are claims 2, and X8 is saturated or unsaturated C1-C6 alkyl or alkyl 2. A compound of formula (1) according to claim 1, which is a lekenyl chain. 6. Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2 -oxo-3-buten-1-ylphosphonate, diethyl 4-(3,5-di-t ert-butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-y diisopropyl 4-(3,5-di-tert-butyl-4-hyperphosphonate) Droxyphenyl)-2-oxo-3-buten-1-ylphosphonate, dibuti 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxy So-3-buten-1-ylphosphonate, dimethyl 4-(3,5-di-tert -butyl-4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3-butyl ten-1-ylphosphonate, diethyl 4-(3,5-di-tert-butyl- 4-hydroxyphenyl)-1,1-dimethyl-2-oxo-3-butene-1- ylphosphonate, diisopropyl 4-(3,5-di-tert-butyl-4- hydroxyphenyl)-1,1-dimethyl-2-oxo-3-buten-1-yl Phosphonate dimethyl 4-(3,5-di-tert-butyl-4-hydroxyph) (phenyl)-1-methyl-2-oxo-3-buten-1-ylphosphonate, diethyl Chyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-methyl Thyl-2-oxo-3-buten-1-ylphosphonate, dimethyl 4-(3,5 -di-tert-butyl-4-hydroxyphenyl)-3-methyl-2-oxo -3-buten-1-ylphosphonate, diethyl 4-(3,5-di-tert- Butyl-4-hydroxyphenyl)-3-methyl-2-oxo-3-butene-1 -ylphosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydro (roxyphenyl)-3-(n-butyl)-2-oxo-3-buten-1-ylpho sulfonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl) (phenyl)-3-(n-pentyl)-2-oxo-3-buten-1-ylphosphone dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl) )-2-oxo-3-phenyl-3-buten-1-ylphosphonate, diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxo -3-phenyl-3-buten-1-ylphosphonate, dimethyl 4-(3,5- di-tert-butyl-4-hydroxyphenyl)-2-oxo-1-butylpho Suphonate, Diethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2 -oxo-1-butylphosphonate, Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1 , 1-dimethyl-2-oxo-1-butylphosphonate, diethyl 4-(3,5 -di-tert-butyl-4-hydroxyphenyl)-1,1-dimethyl-2- Oxo-1-butylphosphonate, diethyl 6-(3,5-di-tert-butyl -4-hydroxyphenyl)-2-oxo-3,5-hexadien-1-yl Phosphonate, dimethyl 6-(3,5-di-tert-butyl-4-hydroxy phenyl)-1,1-dimethyl-2-oxo-3,5-hexadien-1-yl Phosphonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxy phenyl)-1,1-dimethyl-2-oxo-3,5-hexadien-1-yl Phosphonate, dimethyl 2-(3,5-di-tert-butyl-4-hydroxy phenyl)-2-oxo-1-ethylphosphonate, N,N,N,N-tetramethyl 4-(3,5-di-tert-butyl-4-hydro (roxyphenyl)-2-oxo-3-buten-1-ylphosphonate, dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-di Oxo-1-butylphosphonate, dimethyl 6-(3,5-di-tert-butyl (4-hydroxyphenyl)-2,4-dioxo-5-hexen-1-ylpho sulfonate, diethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl) (phenyl)-2,4-dioxo-5-hexen-1-ylphosphonate, ethyl 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,4-di Oxo-1-hexylphosphonate, dimethyl 6-(3,5-di-tert-butyl thyl-4-hydroxyphenyl)-2,4-dioxo-hexylphosphonate, Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3 -Ethyl-2-oxo-3-buten-1-ylphosphonate, dimethyl 4-(3 ,5-di-sec-butyl-4-hydroxyphenyl)-2-oxo-3-bute ion-1-ylphosphonate, diethyl 4-(3,5-di-sec-butyl-4- Hydroxyphenyl)-2-oxo-3-buten-1-ylphosphonate, dimethyl Chyl 4-(3,5-di-tert-butyl-4-methoxyphenyl)-2-oxy So-3-buten-1-ylphosphonate, dimethyl 4-(3,5-di-tert -butyl-4-hydroxyphenyl)-2-oxo-3-buten-1-ylthio Nophosphonate, 2-[4-(3,5-di-tert-butyl-4-hydroxy) phenyl)-2-oxo-3-buten-1-yl](2-oxo-1,3,2- dioxaphosphorinane), dimethyl 4-(3,5-di-tert-butyl-4- Hydroxyphenyl)-4-oxo-2-buten-1-ylphosphonate, diene Chyl-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-o xo-2-buten-1-ylphosphonate, diethyl 2-(3,5-di-ter t-Butyl-4-hydroxyphenyl)-2-oxo-1-ethylphosphonate , diisopropyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl )-2-oxo-1-ethylphosphonate, dimethyl 3-(3,5-di-ter t-Butyl-4-hydroxyphenylthio)-2-oxo-1-propylphosphor diethyl 3-(3,5-di-tert-butyl-4-hydroxyphenylene) ruthio)-2-oxo-1-propylphosphonate, dimethyl 3-(3,5-di -tert-butyl-4-hydroxyphenylthio)-3,3-dimethyl-2- Oxo-1-propylphosphonate, diethyl 3-(3,5-di-tert-butyl methyl-4-hydroxyphenylthio)-3,3-dimethyl-2-oxo-1-p Lopylphosphonate, dimethyl 5-(3,5-di-tert-butyl-4-hydride) (roxyphenylthio)-2,4-dioxo-1-bentylphosphonate, diethyl 5-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2, 4-dioxo-1-pentylphosphonate, dimethyl 4-(3,5-di-ter t-Butyl-4-hydroxyphenyl)-2-hydroxy-3-buten-1-y dimethyl 4-(3,5-di-tert-butyl-4-hydroxy) Cyphenyl)-2-hydroxy-1-butylphosphonate, Dimethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2 -hydroquine-1-ethylphosphonate, Dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2 , 4-dihydroxy-1-butylphosphonate, dimethyl 3-(3,5-di-t ert-butyl-4-hydroxyphenylthio)-2-hydroxy-1-propyl dimethyl 4-(3,5-di-tert-butyl-4-hydroxy) Cyphenyl)-1,3-bucdien-1-ylphosphonate, dimethyl 4-(3 ,5-di-tert-butyl-4-hydroxyphenyl)-2-(acetyloxyphenyl) di)-1-butylphosphonate, dimethyl 4-(3,5-di-tert-butyl -4-hydroxyphenyl)-2-(hexanoyl ookine)-1-butylphospho dimethyl 4-(3,5-di-tert-butyl-4-hydroxyphenyl) )-2-(4-pentenoyloxy)-1-butylphosphonate, dimethyl 3 -(3,5-di-tert-butyl-4-hydroxyphenylthio)-2-(a cetyloxy)-1-propylphosphonate, dimethyl 3-(3,5-di-te rt-butyl-4-hydroxyphenylthio)-2-(hexanoyloxy)- of formula (I) according to claim 1 selected from the group consisting of 1-propylphosphonate. Compound. 7. A is (CH2)t, (CH=CH)n-CH=CX3, (CH2)t-CH X3, S-(CH2)t-(CH=CH)n, S-CX4X5, where n , t, X3, X4 and X5 are the same as described in claim 1. A process for producing an alkylphosphonate III: ▲There are mathematical formulas, chemical formulas, tables, etc.▼III [Here, B is CH2, CHX6 or is CX6X7, and X6, X7, Y, Z1 and Z2 are the same as described in claim 1 ] of n-butyllithium or lithium di-ion at a temperature between -78°C and -40°C. reacted with sopropylamide and then in situ Lithium anion in tetrahydrofuran at a temperature between -78°C and 25°C. Ester II: ▲There are mathematical formulas, chemical formulas, tables, etc.▼II [Here, X1, X2, and G are Same as described, A is (CH2)t, (CH=CH)n-CH=CX3, (CH2) t-CHX3, S-(CH2)t-(CH=CH)n, S-CX4X5 4. A process for producing a compound of formula (I) according to claim 3, characterized in that the compound is reacted with 8. A method for producing a compound of formula (I), wherein A is (CH=CH)n-CH=CX3. So, formula IV: ▲There are mathematical formulas, chemical formulas, tables, etc.▼IV [In the formula, G, X1, X2, and n are in claim 1 The aldehyde shown in In the presence of phosphorus in tetrahydrofuran at a temperature between -20°C and 66°C, formula V: ▲There are mathematical formulas, chemical formulas, tables, etc.▼V [In the formula, X3, B, Y, Z1, and Z2 are the same as described in claim 1] of the compound of formula (I) according to claim 3, characterized in that it is reacted with a sulfonate. Manufacturing method. 9. A method for producing a compound of formula (I), wherein A is (CH2)t-CHX3, the compound Object V: ▲There are mathematical formulas, chemical formulas, tables, etc.▼V [Here, X3, B, Y, Z1 and Z2 are the same as described in claim 1] is first mixed with water. sodium chloride and n-butyllithium, and then formula VI: ▲ mathematical formula, chemical formula, There are tables, etc. ▼ VI [where G, X1, X2, and t are the same as those in claim 1] The indicated halide in tetrahydrofuran at -30°C and in tetrahydrofuran. Formula (I) according to claim 3, characterized in that the reaction is carried out at a temperature of boiling point (66 ° C.) A method for producing the compound. 10. A is (CH=CH)n-CH=CH-C(O)-CHX3, (CH2)p -CH=CH-C(O)-CHX3, (CH2)t-C(O)-CHX3, S( CH2)t-(CH=CH)n-C(O)-CHX3 or S-CX4X5-C (O)-CHX3, where n, p, t, X3, X4 and X5 are Claim 1 A method for producing a compound of formula (I) which is the same as described in , wherein compound V: ▲ mathematical formula, chemical There are formulas, tables, etc.▼V [Here, X3, B, Y, Z1, and Z2 are the same as described in claim 1] at -78°C. At a temperature between 0°C, first with sodium hydride and then with n-butyllithium or -6 in tetrahydrofuran. At temperatures between 0°C and 25°C, Ester VII: ▲Mathematical formulas, chemical formulas, tables, etc. ▼ [Here, E is (CH=CH)n-CH=CH, (CH2)p-CH=CH, ( CH2)t or S(CH2)t-(CH=CH)n, S-CX4X5, n, p, t, X4, and X5 are the same as described in claim 1] A method for producing a compound of formula (I) according to claim 3, which comprises reacting with. 11. The ketone functionality is isolated in methanol, ethanol or isopropanol by - Complex halides, sodium borohydride or Formula (I) according to claim 4, characterized in that is reduced with lithium borohydride. A method for producing the compound. 12. The corresponding acyloxy-phosphonate compound was prepared from the appropriate acid anhydride ((X8 Characterized by esterification with CO)2O) or acid chloride (X8-COC1) A method for producing a compound of formula (I) according to claim 5. 13. A therapeutically effective amount of a compound of formula (I) according to claim 1 is administered in a pharmaceutically acceptable amount. A pharmaceutical composition characterized in that it is formed in combination with a carrier. 14. A compound of formula (I) according to claim 1 for use in therapy. 15. Formula according to claim 1 for use in the treatment of atherosclerosis Compound (I).