JP2003507356A - New stilbenes with vascular damage activity - Google Patents

Abstract

(57) [Summary] Formula (1) Wherein R ¹ , R ² , and R ³ are each independently alkyl, and R ⁴ is alkyl, haloalkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or halo; ⁵ is hydrogen, alkoxy, alkyl, alkylthio, hydroxy, or halo, a novel cis-stilbene as disclosed, and a pharmaceutically acceptable salt of the cis-stilbene, or a phosphate ester such as A group of prodrugs. These compounds have vascular damaging activity and are therefore of potential value in the treatment of diseases where reversal of angiogenesis may be therapeutically beneficial.

Description

Detailed Description of the Invention

The formation of new vasculature by angiogenesis is a hallmark of key abnormalities in several diseases (J Folkman, New England Journal of.
Medicine 333, 1757-1763 (1995)). For example, for a growing solid tumor, the solid tumor must develop its own blood supply, which it depends critically on the provision of oxygen and nutrients. If this blood supply were mechanically cut off, the tumor would be necrotic. Angiogenesis is also
Clinical features of skin disorders in psoriasis, invasive pannus in the joints of patients with rheumatoid arthritis, and atherosclerotic plaques. Retinal neovascularization is an abnormality in macular degeneration and diabetic retinopathy. In all of these diseases, reversal of angiogenesis by damaging the endothelium of newly formed blood vessels is expected to have beneficial therapeutic effects.

Compounds that can damage the neovasculature have advantages in the treatment of disease. For example, attacking the vasculature of a tumor has some important advantages over direct attack on the tumor. In individual endothelial cells of tumors, the vasculature is genetically more stable than the vasculature of the tumor itself, and thus less likely to be resistant to damaging agents. In this way, a major problem in conventional anti-tumor chemotherapy is that of drug resistance, which is avoided by this method. Moreover, because the endothelial cells of the tumor vasculature are similar among different solid tumor types, unlike the tumor cells themselves, vascular damaging agents can attack a wide range of tumor types.

Combretastatin A1, Combretastatin A4 (DJ Chaplin
et al. , British J .; Cancer 27, S86-S88 (
1996)), and combretastatin A4 phosphate (DJ Chaplin).
et al. , Anticancer Research 19, 189-1
96, (1999)), many tubulin-binding agents, including stilbenes, are known to selectively damage the neovasculature of solid tumors in animal models.
Although there are reports of activity of other similar compounds of Combrestatin A4 in the tubulin binding assay, there are still no reports of vascular damage activity of similar compounds in cytotoxicity assays and tumor models. The activity of tubulin-binding compounds on in vitro assays is a weak predictor of selective vascular damage activity, and the activity of such compounds in vivo also has a direct anti-mitotic effect on the tumor itself. Since it can be mediated by, published reports fail to predict the selective vascular damage activity in known or novel analogues of combretastatin. In this way, compounds that have the advantages of the selective anti-vascular mechanisms listed above, rather than acting through a direct effect on the tumor tissue itself, are not clear.

The inventors have discovered a series of novel cis-stilbenes with a vascular damage activity. These compounds clearly damage the endothelium of newly formed blood vessels, especially those associated with solid tumors, without affecting the endothelium of established blood vessels of normal, host species. Such compounds are useful in the prevention and treatment of cancers associated with solid tumors and in the inappropriate formation of new vasculature such as diabetic retinopathy, psoriasis, rheumatoid arthritis, macular degeneration, and atherosclerotic plaque formation. Beneficial in certain other diseases.

Known vascular damage stilbenes, Combrestatin A1, Combrestatin A4
, And Combrestatin A4 phosphate have a 4-methoxy group on the "B" ring.
The compounds of the present invention lack a 4-methoxy group in the ring corresponding to the "B" ring of Combrestatin A4. Some studies have shown that 4 in the B ring of Combrestatin A4
It is proposed that alternative groups substituting for the -methoxy group may significantly reduce biological activity.

J. Med. In Chem 1991, 34, 2579-2588, Cu
shman et al., for analogues of Combrestatin A4, "the presence of the 4-methoxy group in the B ring plays a very important role in this compound, which is very cytotoxic". Substitution of the 4-methoxy group with chlorine gave compounds that were ineffective, for example by three to four orders of magnitude, against a panel of five different cell lines.

J. Med. Chem. 1998, 41, 3022-3032, Oh
Sumi et al., Combrestatin A4, in which substitution of the B-ring 4-methoxy group with either a methyl group or a chlorine atom resulted in 8.5- and 13.5-fold reductions in biological potency, respectively. Of anilino analogues of.

Brit. J. Similarly in Cancer 1995, 71, 705-711, Woods et al. Disclose analogs of combretastatin with reduced potency. For example, 4-methyl compounds show a 3.5-36 fold reduction in potency against four cell lines compared to 4-methoxy compounds.

It is unexpected from the above studies that compounds in which the 4-methoxy group of the B ring is substituted may retain anti-vascular activity. It is not particularly unexpected that substitution of the methoxy group on the B ring of Combrestatin A4 may result in compounds with similar potency as vascular injury agents.

[0010]   Thus, according to one aspect of the invention, the inventors

[0011]

[Chemical 2] Wherein R ¹ , R ² , and R ³ are each independently alkyl, R ⁴ is alkyl, haloalkyl, alkenyl, alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or halo, and R ⁵ is , Hydrogen, alkoxy, alkyl, alkylthio, hydroxy, or halo, as well as pharmaceutically acceptable salts, solvates, hydrates, and prodrugs of the compounds.

As used herein, the term “alkyl”, alone or in combination, represents one to seven, preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, and pentyl. Means a straight or branched chain alkyl group containing up to 4 carbon atoms. Examples of alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, and t-butoxy.

[0013]   The term "halogen" means fluorine, chlorine, bromine, or iodine.

Alkenyl groups are, for example, methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, and t-butylene, such as olefins containing from 2 to 7 carbon atoms. It may be a group. The alkynyl group may be, for example, an ethynyl, propynyl, or butynyl group.

Salt formation is possible when one or more functional groups in the compound of formula (1) are sufficiently basic or acidic. Suitable salts are, for example, hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkyl sulphonates, aryl sulphonates, acetates, benzoates, citrates, maleic acid. Inorganic bases including salts, fumarates, succinates, lactates, and acid addition salts including tartrates, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts. And pharmaceutically acceptable salts of salts derived from organic amines such as salts of morpholine, piperidine, or dimethylamine.

The prodrug of the present invention is a compound which produces a compound of formula (1) upon administration to a mammal. Such prodrugs can be converted in mammals, for example, by hydrolysis. The prodrug is preferably an ester derivative of the phenolic hydroxyl group contained in the compound of formula (1) such as, for example, phosphoric acid ester, carboxylic acid ester, sulfuric acid ester and carbonic acid ester.

Preferred compounds of the present invention are compounds of formula (1) wherein R ¹ , R ² and R ³ are all methyl
And a prodrug of the compound.

[0018]   Further preferred compounds of the invention are R¹, R^Two, And R^ThreeAre all methyl, R ⁵ Are compounds of formula (1) in which is hydrogen, as well as prodrugs of the compounds.

Still further preferred compounds of the present invention are compounds of formula (1) wherein R ¹ , R ² and R ³ are all methyl, R ⁵ is hydrogen and R ⁴ is alkyl or halo. , And prodrugs of the compound.

The preferred prodrug of the present invention is a phosphate ester. A particularly preferred prodrug of the present invention is dihydrogen phosphate ester.

A specifically preferred compound of the invention is (Z) -1- (3-hydroxy-4-methylphenyl) -2- (3,4,5-
Trimethoxyphenyl) ethene (Z) -2-methyl-5- [2- (3,4,5-trimethoxyphenyl) ethenyl] phenyl = dihydrogen = phosphate.

The compounds of this invention may be prepared by any process known to those of ordinary skill in the art. The compounds of formula (1) can be prepared by a number of processes described generally below, and more specifically in the examples below. In the general preparations described below, it may be necessary to use protecting groups that are removed during the final steps of the synthesis. The proper use of such protecting groups and the process of removal of those protecting groups will be readily apparent to those skilled in the art. In the description of the processes that follow, the symbols R ¹ , R ² , R ³ , R ⁴ , and R ⁵ , when used in the depicted formulas, unless otherwise indicated, represent the groups described above with respect to formula (1). Is to be understood.

In one general example, treatment with an aldehyde of formula (3), wherein R ⁶ is a protecting group, to provide an intermediate of formula (4), is followed by about −100 ° C. to about 30 ° C. Alkyllithium, such as n-butyllithium or t-butyllithium, in an ether solvent, such as diethyl ether or tetrahydrofuran, or a hydrocarbon solvent, such as toluene, at a temperature between By the Wittig olefin synthesis involving the reaction of the phosphonium salt of formula (2) with a strong base which is a metal hydride such as sodium hydride, the formula (1
Compounds of) can be prepared. The synthesis of the compound of formula (1) is then completed by removal of the group R ⁶ . Suitable protecting groups R ⁶ include trialkylsilyl and allyl, for example t-butyldimethylsilyl. When R ⁶ is a trialkylsilyl group, the protecting group is protected at a temperature of about −30 ° C. to about 40 ° C., conveniently at or near ambient temperature, in an ether solvent such as tetrahydrofuran, It may be removed by treatment with a quaternary ammonium fluoride such as, for example, tetrabutylammonium fluoride. When R ⁶ is an allyl group, it is converted to an allyl scavenger such as morpholine at about −40 ° C.
A chlorinated solvent at a temperature of 0 ° C., conveniently at or near ambient temperature,
It may be removed by treatment with a complex of palladium (0), eg tetrakis (triphenylphosphine) Pd (0), in a solvent, eg dichloromethane.

[0024]

[Chemical 3] The aldehyde of formula (3) can be prepared by any process known to those skilled in the art. In one general example, an aldehyde of formula (3) can be prepared from an alcohol of formula (5) by oxidation with a suitable oxide. Suitable oxidizing agents include Dess-Martin reagent and manganese dioxide. Alcohols of formula (5) can be prepared by application of standard methods of organic synthesis involving selective protection of phenol of formula (6). The protecting group R ⁶ is a trialkylsilyl group such as t
-Butyldimethylsilyl, for example by treatment with tert-butylchlorodimethylsilane, at a temperature between about -100 ° C and about 40 ° C,
In an ether solvent such as diethyl ether or tetrahydrofuran, or in a hydrocarbon solvent such as toluene such as n-.
An alcohol of formula (5) is prepared by treatment of a phenol of formula (6) with an alkyllithium such as butyllithium or t-butyllithium, or a strong base which is a metal hydride such as sodium hydride. You may.

Phenols of formula (6) are known or may be prepared from known compounds using standard methods of organic synthesis.

[0026]

[Chemical 4] Compounds of formula (1) may be prepared from other compounds of formula (1) by chemical modification. Examples of such chemical modifications that may be applied include standard alkylation,
Halogenation, oxidation, and coupling reactions. These reactions may be used to add new substituents or to modify existing substituents.

Prodrugs of compounds of formula (1) may be prepared by any process known to those skilled in the art. Processes for the preparation of prodrugs of compounds of Formula 1 include standard acylation, sulfation, and phosphorylation reactions. In one common example,
A dihydrogen phosphate ester of a compound of formula (1) is treated with, for example, hydrochloric acid in a chlorinated solvent such as dichloromethane at a temperature of about -20 ° C to about 40 ° C, conveniently at room temperature. Or the corresponding di-t- with acid which is trifluoroacetic acid
It can be prepared by treatment with butyl phosphate.

The compounds according to the invention are capable of destroying the tumor vasculature as well as the newly formed vasculature while leaving the normal mature vasculature unaffected. The ability of the compound to act in this manner may be determined by the tests described below.

Thus, the compounds according to the invention are useful in the prevention and treatment of cancers associated with solid tumors and in such diseases as diabetic retinopathy, psoriasis, rheumatoid arthritis, atherosclerosis and macular degeneration. A particular use is in the prevention and treatment of diseases in which proper angiogenesis occurs.

The compounds of the invention may be administered as a monotherapy or in combination with other treatments. Thus, the present invention comprises a composition for the treatment of angiogenesis, which composition comprises an effective amount of cis-stilbene as defined above or a prodrug of cis-stilbene thereof. The invention also comprises the use of cis-stilbene as defined above, or a prodrug of cis-stilbene thereof, in the preparation of a composition for the treatment of angiogenesis. For the treatment of solid tumors, a compound of the invention is used in combination with radiation therapy or with other anti-tumor agents such as mitotic inhibitors which are, for example, vinblastine, vincristine, vinorelbine, paclitaxel and docetaxel, Alkylating agents, such as cisplatin, and carboplatin, such as melphalan, chlorambucil, busulfan, ifosfamide, and cyclophosphamide, such as methotrexate, 5-fluorouracil, cytosine rabinoside, gemcitabine, and hydroxyurea. Antimetabolites such as bleomycin, doxorubicin, daunomycin, epirubicin,
Antitumor antibiotics that are idarubicin, mitomycin-C, dactinomycin, and mithramycin, such as enzymes that are asparaginases, such as topoisomerase inhibitors that are etoposide, teniposide, topotecan, and isotenotecan,
For example, a thymidylate synthase inhibitor that is raltitrexed, a biological response modifier that is an interferon, such as edrecolomab, and an antibody that is trastuzumab, such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, anastrozole, letrazole, borazole, Antihormones that are exemestane, flutamide, nilutamide, and bicalutamide, such as EGFr tyrosine kinase inhibitors, VEGFr kinase inhibitors, and PDGF
an anti-growth factor compound which is an r-tyrosine kinase inhibitor, and angiostatin,
It may be administered in combination with endostatin and one selected from anti-angiogenic agents such as thalidomide. Such combination therapy may involve the simultaneous or sequential application of the individual components of the therapy.

For the prevention and treatment of disease, the compounds according to the invention may be administered as a pharmaceutical composition selected with regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutical compositions may take any form suitable for oral, buccal, nasal, topical, rectal or parenteral administration and may be prepared in conventional manner using conventional excipients. Good. For oral administration, for example, the pharmaceutical composition may take the form of tablets or capsules. For nasal administration or administration by inhalation, the compounds may conveniently be delivered as a powder or solution. Topical administration may be like ointments or emulsions and rectal administration may be like suppositories. For injection therapy (including intravenous, subcutaneous, intramuscular, intravascular, or infusion), the composition may take the form of, for example, a sterile solution, suspension, or emulsion.

The dose of a compound of the invention required for the prevention or treatment of an individual condition is
It will vary depending on the compound selected, the route of administration, the species and severity of the condition, and whether the compound is to be administered alone or in combination with another drug. Thus, the precise dose will be determined by the administering physician, but a typical daily dose will be in the range of 0.001 to 100 mg / kg, preferably 0.1 to 10 mg / kg. It may be.

[0033]   [Biological activity]   The following tests were used to demonstrate the activity of the compounds according to the invention.

[0034]   (Activities on tumor vasculature measured by fluorescent dyes)   The following experiments further demonstrate the ability of compounds to damage the tumor vasculature.

The functional vascular volume of tumors in mice giving rise to CaNT tumors was determined by Smit.
h et al. (Brit J Cancer 57, 247-253, 1988)
Was measured using the fluorescent dye Hoechst 33342 according to At least 3 animals were used in the control and treatment groups.

Fluorescent dye was dissolved in 6.25 mg / ml saline and injected intravenously at 10 mg / kg 24 hours after intraperitoneal drug treatment. One minute later, the animals were killed and the tumors were excised and frozen. 10 μm sections were cut at three different levels,
It was observed under UV illumination with a microscope equipped with Olympus external fluorescence. The blood vessels are identified by the fluorescent contours of the blood vessels, and the volume of the blood vessels is determined by Chalkle.
Quantification was done using a scoring system based on the description by y (J Natl Cancer Inst, 4, 47-53, 1943). All estimates were based on counting a minimum of 100 regions from sections cut at 3 different levels. An example of the activity of the compounds of the invention in this test is given in the table

[0037]

[Table 1] Give to.

The following non-limiting examples illustrate the invention. (Example 1) (Z) -1- (3-hydroxy-4-methylphenyl) -2- (3,4,5-trimethoxyphenyl) ethene 1- (3-tert-butyldimethylsilyloxy-4 at room temperature -Methylphenyl) -2- (3,4,5-trimethoxyphenyl) ethene (491 mg)
In anhydrous tetrahydrofuran (10 ml) was slowly treated with a 1.1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.1 ml). After 30 minutes, crushed ice (5 ml) and diethyl ether (30 ml) were added and the aqueous phase was extracted with diethyl ether (5 ml 5 times). The combined extracts were washed with water (3 x 10 ml) and brine (10 ml), dried (MgSO4).
, Concentrated under reduced pressure to give a solid. Recrystallisation from ethyl acetate / hexanes gave the title compound (208 mg) as a white solid. Melting point 123 to 125 ° C., nm
r: δH (500 MHz, d6-DMSO) 2.07 (s, 3H), 3.57
(S, 6H), 3.62 (s, 3H), 6.40 (d, J = 12Hz, 1H),
6.46 (d, J = 12 Hz, 1H), 6.56 (s, 2H), 6.61 (dd
, J = 8 Hz, 2 Hz, 1H), 6.76 (d, J = 1.7 Hz, 1H), 6.
98 (d, J = 8 Hz, 1H), 9.21 (s 1H) 1- (3-tert-butyldimethylsilyloxy-4-methylphenyl) -2- (3, used as starting material in the above preparation. 4,5-Trimethoxyphenyl) ethene was prepared as follows.

A suspension of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (848 mg) in dry tetrahydrofuran (50 ml) at −78 ° C. was added to n.
-Butyllithium (0.9 ml of 1.8 M hexane solution) was added dropwise, the mixture was allowed to warm to -40 ° C and allowed to stir for 1 hour. The mixture was cooled again to −78 ° C. and a solution of 3-tert-butyldimethylsilyloxy-4-methylbenzaldehyde (390 mg) in tetrahydrofuran (40 ml) was added slowly. After a further 2 hours, the mixture was allowed to warm to room temperature before being poured into ice water (20 ml). The aqueous layer was extracted with diethyl ether (5 times 20 ml),
The combined extracts were washed with water (3 x 20 ml) and brine (2 x 20 ml), dried (MgSO4) and concentrated under reduced pressure to give an oil. Purification by chromatography on silica gel eluting with petroleum ether / ethyl acetate (90:10) gave 1- (3-tert-butyldimethylsilyloxy-4-methylphenyl) -2- (3,4,5-triethyl). Methoxyphenyl) ethene (456 mg) was obtained as a red oil.

The 3-tert-butyldimethylsilyloxy-4-methylbenzaldehyde used as a starting material in the above preparation was prepared as follows.

Dess-Martin periodinane (187 mg) in dichloromethane (4 ml)
The solution was treated slowly with a solution of 3-tert-butyldimethylsilyloxy-4-methylbenzyl alcohol (100 mg) in dichloromethane (4 ml) and the mixture was stirred at room temperature for 1 hour. Diethyl ether (10 ml) was added followed by aqueous sodium thiosulfate solution (10 ml) and the mixture was stirred for 15 minutes.
The aqueous layer was extracted with diethyl ether (5 x 20 ml) and the combined extracts were extracted with aqueous sodium thiosulfate (3 x 10 ml), water (3 x 10 ml) and brine (2 x 10 ml). Washed, dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. Purification by chromatography on silica gel eluting with petroleum ether / diethyl ether (50:50) gave 3-tert-butyldimethylsilyloxy-4-methylbenzaldehyde (85 mg).

The 3-tert-butyldimethylsilyloxy-4-methylbenzyl alcohol used as a starting material in the above preparation was prepared as follows. -78
A solution of 3-hydroxy-4-methylbenzyl alcohol (275 mg) in dry tetrahydrofuran (15 ml) at 0 ° C was slowly treated with n-butyllithium (1.2 ml of 1.8 M hexane solution), warmed to room temperature and further 30 The mixture was stirred for 15 minutes before allowing to stir for 1 minute. A solution of tert-butylchlorodimethylsilane (287 mg) in tetrahydrofuran (10 ml) was added and the mixture was stirred for 16 hours. Water (20 ml) was added and the mixture was extracted with diethyl ether (20 ml 5 times), water (10 ml 2 times) and brine (20 ml).
Washed with, dried (MgSO4) and concentrated under reduced pressure. Purification by chromatography on silica gel eluting with petroleum ether / diethyl ether (50:50) gave 3-tert-butyldimethylsilyloxy-4-methylbenzyl alcohol (390 mg).

Example 2 (Z) -2-Methyl-5- [2- (3,4,5-trimethoxyphenyl) ethenyl] phenyl = dihydrogen = phosphate Trifluoroacetic acid (0.22 mL, 2. 95 mmol), (Z) -2-methyl-5- [2- (3,4,5-trimethoxyphenyl) ethenyl] phenyl = di-tert-butyl phosphate (401 mg, 0.82 mmol) and dichloromethane (16 mL). ) Was added dropwise to the stirred solution. The mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was azeotroped with toluene for 4 hours. The colorless oil was titrated with ether to give the title compound as a white solid (181m).
g, 58%). Melting point 109 to 113 ° C., nmr: δH (500 MH
z, d6-DMSO) 2.39 (s, 3H), 3.81 (s, 6H), 3.8
7 (s, 3H), 6.69 (d, J = 12Hz, 1H), 6.74 (d, J = 1)
2Hz, 1H), 6.78 (s, 2H), 7.07 (d, J = 8Hz, 1H),
7.28 (d, J = 8 Hz, 1H), 7.49 (s, 1H), 9.0 (bs, 2)
H) (Z) -2-Methyl-5- [2- (3,4,5-trimethoxyphenyl) ethenyl] phenyl = di-tert-butyl phosphate was prepared as follows.

Di-tert-butyl phosphoramidite (4
98 mg, 2.00 mmol) under nitrogen (Z) -1- (3-hydroxy-4-methylphenyl) -2- (3,4,5-trimethoxyphenyl) ethene in dichloromethane (3 mL). (300 mg, 1.00 mmol) and 1H-tetrazole (182 mg, 2.60 mmol). After 2 hours, magnesium monoperoxyphthalate hexahydrate (1.24 g, 2.00 mmol) was added in several portions. After stirring for a further 2 hours, the reaction mixture was partitioned between ethyl acetate and water, the aqueous layer was extracted (ethyl acetate x 2) and the combined organic extracts were washed (water x 2, brine x 1), Dry (MgSO ₄ ) and concentrate in vacuo. Flash chromatography eluting with 33% ethyl acetate / hexanes gave (Z) -2-methyl-5- [2- (3,4,5-trimethoxyphenyl) ethenyl] phenyl =
Di-tert-butyl phosphate (401 mg, 82%) was obtained as a yellow oil.

Example 3 (Z) -1- (4-Fluoro-3-hydroxyphenyl) -2- (3,4,5)
-Trimethoxyphenyl) ethene This compound was prepared in a similar manner to the compound of Example 1, 3,4,5-trimethoxybenzyltriphenylphosphonium bromide and 3-tert-butyldimethylsilyloxy-4-fluorobenzaldehyde (340 mg). ) Was directly isolated from the Wittig reaction between The title compound (80 mg) was obtained as a colorless oil. nmr: (300 MHz, d6-DMSO) 3.59 (s, 6H), 3
． 63 (s, 3H), 6.46 (d, J = 12Hz, 1H), 6.48 (d, J
= 12 Hz, 1H), 6.54 (s, 2H), 6.68 (m, 1H), 6.90
(Dd, J = 8.8, 2.1 Hz, 1H), 7.06 (dd, J = 11.4, 8)
． 4 Hz, 1H), 9.80 (s, 1H) The following compounds were prepared in an analogous manner to the compound of Example 1.

Example 4 (Z) -1- (4-chloro-3-hydroxyphenyl) -2- (3,4,5-
Trimethoxyphenyl) ethene (Z) -1- (3-tert-butyldimethylsilyloxy-4-chlorophenyl) -2- (3,4,5-trimethoxyphenyl) ethene (240 mg) to give the title compound (121 mg ) Was obtained as a colorless oil. nmr: (300MH
z, d6-DMSO) 3.59 (s, 6H), 3.63 (s, 3H), 6.4
9 (m, 2H), 6.54 (s, 2H), 6.71 (dd, J = 8.2, 0.9)
Hz, 1H), 6.93 (d, J = 0.9Hz, 1H), 7.25 (d, J = 8)
． 2 Hz, 1 H), 10.11 (bs, 1 H), m / e 320 (M +) (Example 5) (Z) -1- (4-ethyl-3-hydroxyphenyl) -2- (3,4,5) −
Trimethoxyphenyl) ethene (Z) -1- (3-tert-butyldimethylsilyloxy-4-ethylphenyl) -2- (3,4,5-trimethoxyphenyl) ethene (926 mg) to the title compound ( 208 mg) was obtained as a white solid. Melting point 105 to 107
° C, nmr: δH (300 MHz, CDCl3) 1.02 (t, J = 7.6H
z, 3H), 2.6 (q, J = 7.5 Hz, 2H), 3.7 (s, 6H), 3.
8 (s, 3H), 4.6 (bs, 1H), 6.4 (d, J = 12Hz, 1H),
6.5 (d, J = 12 Hz, 1H), 6.5 (s, 2H), 6.7 (s, 1H)
, 6.8 (d, J = 7.6 Hz, 1H), 7.0 (d, J = 7.6 Hz, 1H)

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) // C07M 9:00 C07M 9:00 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ) , MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, Z, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ , LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZWF F-term (reference) 4C086 AA01 AA02 AA03 DA34 MA04 MA28 MA35 MA52 MA55 NA14 ZB26 4C206 AA01 AA02 AA03 CA34 MA04 MA48 MA55 MA72 MA75 NA14 ZB26 4H006 AA01 AB23 GP03 GP12 GP22 4H050 AA01 AB23

Claims (10)

[Claims] 1. The formula: Wherein R ¹ , R ² and R ³ are each independently alkyl, and R ⁴ is alkyl, haloalkyl, alkenyl, alkynyl, alkylthio,
Cis-stilbene, which is alkylsulfinyl, alkylsulfonyl, or halo, and R ⁵ is hydrogen, alkoxy, alkyl, alkylthio, hydroxy, or halo, or a pharmaceutically acceptable salt or solvate of the cis-stilbene. , Hydrates, or prodrugs. 2. The cis-stilbene according to claim ¹ , wherein R ¹ , R ² and R ³ are all methyl. 3. The cis-stilbene according to claim 2, wherein R ⁵ is hydrogen and R ⁴ is alkyl or halo. 4. (Z) -1- (3-hydroxy-4-methylphenyl) -2
-(3,4,5-trimethoxyphenyl) ethene. 5. A prodrug of cis-stilbene which is the carboxylic acid ester, phosphoric acid ester, sulfuric acid ester, or carbonic acid ester of cis-stilbene according to any one of claims 1 to 3. 6. A prodrug of cis-stilbene, which is the phosphoric acid ester of cis-stilbene according to claim 1. 7. The prodrug according to claim 5, which is a dihydrogen phosphate ester. 8. (Z) -2-Methyl-5- [2- (3,4,5-trimethoxyphenyl) ethenyl] phenyl = dihydrogen = phosphate. 9. A composition for use in the treatment of angiogenesis, the cis-stilbene of claim 1 or claim 5 in an effective amount.
9. A composition comprising a cis-stilbene prodrug according to any one of claims 8 to 8. 10. Use of cis-stilbene according to any one of claims 1 to 4 or a prodrug of cis-stilbene according to any one of claims 5 to 8 in the preparation of a composition for the treatment of angiogenesis. Method.