KR20050062581A - Novel bioactive diphenyl ethene compounds and their therapeutic applications - Google Patents

Abstract

This invention provides a novel group of diphenyl ethene derivatives, pharmaceutically acceptable salts thereof, the process of making these compounds, their pharmaceutical composition and the use of these compounds as agents for treating immune, inflammatory and auto-immune diseases.

Description

Novel bioactive diphenyl ethene compounds and their therapeutic uses {NOVEL BIOACTIVE DIPHENYL ETHENE COMPOUNDS AND THEIR THERAPEUTIC APPLICATIONS}

Stilbene derivatives are well known in the art to have a wide range of activities and are widely distributed everywhere. There is an increasing interest in stilbene derivatives due to the range of activities observed in some synthetic stilbenes as well as some natural stilbenes. The stilbene derivative 3,5,4'-trihydroxystilbene, commonly known as resveratrol, has been reported to have two isomers (cis or trans) both having a range of biological functions, such as inflammation mediation and cancer chemoprevention. (Jang, et al., 1997, Science, 275, 218, US 6,008,260).

Substitution for various positions on the two phenyl rings of the stilbene base structure can vary widely, for example those having one or two substituents on one or both of the phenyl rings of the stilbene structure (Shudo K , 1988, US4723028; Hensley, KL, et al., WO 99/59561, Kunihiro N., 1983, JP58159410; Genji I., 1995, JP07053359 and GB1465661) and those having three or more substituents on the phenyl rings ( Koichi, S. et al., 1986, EP0170105; Shozo Y., et al., 1986, JP08337523; and Charpentier B. et al., 1992, WO92 / 19583). Compounds having other substituents on the phenyl ring, for example vitamin A (Ney, UM, et al., 1987, Dermatologica, 175: 93-99) and derivatives of vitamin D (WO 00/26167) are widely used in the art. Known. Many publications (WO 92/16486, WO 99/40056, WO 01/95859 and Cushman M. et al. 1992, J. Med. Chem., 35: 2293-2306) have 3,4,5-trime Compounds derived from oxy stilbenes are disclosed. These compounds showed antitumor activity and moderate activity for the regulation of cytokines (WO 01/95859).

Recently, stilbene groups or derivatives thereof having unique substitution patterns of two hydroxyl groups at positions 3 and 5, and substituents therebetween have been disclosed. The pending applications of the inventors are compounds which have inhibitory activity against kinases, compounds with anti-inflammatory activity (WO 01/42231), compounds with T lymphocytes, macrophages, neutrophils and mast cells and which modulate various immune and inflammatory activities ( WO 02/057219). However, to date, no unique substitution pattern on one phenyl group, with substitution by a range of specific substituents on other phenyl groups, in particular fluoro atoms, has not been found to produce compounds with surprising immunomodulatory activity. The present invention relates to such novel stilbene compounds, methods of their synthesis, their unexpected activities, pharmaceutical compositions, and their use for the treatment of diseases associated with these activities.

Summary of the Invention

The present invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof, pharmaceutical compositions of said compounds which have been found to be useful as immunomodulators:

The present invention includes novel compounds of formula (I)

Formula I

Where

R ¹ is selected from the group consisting of unsubstituted or substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl and aralkyl groups, halo and COR ⁹ ;

R ² and R ³ are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl and acyl;

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are not H at the same time and independently H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl and aralkyl groups, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , _wherein n is 0 to 2, OR ¹² , a cyclic and heterocyclic group ; Provided that when R ¹ is an unsaturated group consisting of one to three isoprene unit (s), R ⁶ is not a hydroxy or alkoxy group;

R ⁹ is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl and aralkyl, and NR ¹⁰ R ¹¹ and OR ¹⁰ ;

R ¹⁰ and R ¹¹ are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl and aralkyl;

R ¹² is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl and acyl.

In particular, in the novel compounds of formula I, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl and aralkyl groups, halo, Nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , _where n is 0 to 2, OR ¹² , a cyclic and heterocyclic group One of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is F. The arrangement of the double bonds of the above formula (I) is E or Z.

Very preferred compounds are:

4- [2- (3,5-Dihydroxy-4-i-propylphenyl) ethenyl] benzoic acid (6).

3- [2- (3,5-Dihydroxy-4-i-propylphenyl) ethenyl] benzoic acid (7).

5- [2- (4-hydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol (13).

5- [2- (3,5-dihydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol (15).

5- [2- (2-fluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (37).

5- [2- (3-fluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol (38).

5- [2- (4-fluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol (39).

5- [2- (3,5-difluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol (40).

5- [2- (2,4-difluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (41).

5- [2- (2,6-difluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (42).

2-i-propyl-5- [2- (2,4,6-trifluorophenyl) ethenyl] -1,3-benzenediol (43).

5- [2- (2,3,4,5,6-pentafluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (44).

The invention also includes the use of compounds of formula I as immunomodulators.

The compounds of the present invention can be synthesized using the general procedure disclosed in patent publication WO02 / 057219 with certain modifications. The examples provided herein are illustrative only and are not to be regarded as a limitation of the present invention. In general, the stilbene structure of the compounds of the invention is prepared via a Wittich olefin (Scheme 1) and a heck reaction (Scheme 2). The corresponding 1,3-benzenediol can be obtained by deprotection reaction.

Vitis olefins:

Heck Reaction:

change:

One change to R ¹ is to start with bromotylbene (Scheme 3). The bromide can be converted to other functional groups by Suzuki coupling or bromo-lithium exchange followed by reaction with an electrophile.

The compounds used according to the invention have double bonds in the Z or E configuration to produce trans and cis isomers. The scope of the present invention is intended to include all such isomers as well as mixtures of cis and trans isomers.

Pharmaceutically acceptable salts may be prepared for any compound having the ability to act in the present invention to form such salts. Pharmaceutically acceptable salts may be formed with inorganic and / or organic acids and bases. Suitable acids include, for example, hydrochloric acid, sulfuric acid, nitric acid, benzenesulfonic acid, acetic acid, maleic acid, tartaric acid and the like, which are pharmaceutically acceptable. Pharmaceutically acceptable salts are preferred, but are useful as other salts, particularly when the compounds of the invention are used as medicaments, for example when the preparation of such compounds or the use of non-pharmaceutical types is contemplated.

Compounds of the present invention exhibited a range of immunomodulatory activities demonstrated and confirmed in the following examples. Compounds with immunomodulatory activity are well known in the art and are disclosed in numerous patents and scientific publications. It is generally known and approved in the art that immunomodulatory activity is useful for treating a number of diseases and disorders in animals, including humans. Compounds or compounds having immunomodulatory activity as active ingredients, for example compositions having those disclosed herein, may be used, for example, for clinical implants (eg organ transplants, acute implants or xenografts or allografts). Treatment of diseases such as rejection)) used for the treatment of burns; Protection from ischemic or reperfusion injury, such as during ischemic transplantation or resulting from myocardial infarction, seizures or other causes; Induction of transplant resistance; Arthritis (eg rheumatoid arthritis, psoriatic arthritis or osteoarthritis); Multiple sclerosis; Inflammatory bowel disease such as ulcerative colitis and Crohn's disease; Lupus (systemic lupus erythematosus); Graft versus host disease; T-cell mediated hypersensitivity diseases such as contact hypersensitivity, delayed type of hypersensitivity, and gluten-sensitive bowel disease (celiac disease); psoriasis; Contact dermatitis (including dermatitis caused by vines for example); Hashimoto's thyroiditis; Sjogren's syndrome; Autoimmune hyperthyroidism, eg Grave's disease; Addison's disease (autoimmune disease of the adrenal gland); Autoimmune multiple gland disease (also known as autoimmune multiple gland syndrome); Autoimmune alopecia; Pernicious anemia; Vitiligo; Autoimmune hypothyroidism; Gillian-Barré syndrome; Other autoimmune diseases; Glomerulonephritis, serum disease; hives; Allergic diseases such as respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies; Scleroderma; Mycelial sarcoma; Acute inflammatory response (eg, acute respiratory distress syndrome and ischemic / reperfusion injury); Dermatitis; Alopecia areata; Chronic ray dermatitis; eczema; Behcet's disease; Plantar pustules; Necrotizing pyoderma; Trident syndrome; Atopic dermatitis; Systemic sclerosis; And medicaments useful for the treatment of diseases such as parasclerosis are generally known in the art. In particular, activity against VEGF expression is useful for the treatment of cancer and VEGF related diseases. Inhibition of LTB ₄ induced cell migration is useful as an anti-inflammatory agent.

The present invention therefore provides a method of treating a disease associated with the above-mentioned activity, the method comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I). Other therapeutic agents as known to those skilled in the art can be used with the compounds of the invention in the methods of the invention. In the methods of the invention, such other therapeutic agent (s) may be administered prior to, concurrent with or subsequent to the administration of the compound of the invention.

Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, powders, suppositories, etc.) or liquids (solutions, suspensions or emulsions) in compositions suitable for oral, topical, non-oral or rectal administration. Such formulations may contain the pure compound or together with a carrier or some other pharmaceutically active compound. It may be necessary to sterilize the composition when administered orally.

For topical use, it will be preferable to use it in the form of a cream, ointment, jelly, solution or suspension containing the compound of formula (I) (for this application, topical application will include mouthwashing and brushing).

Doses of about 0.01 mg to about 140 mg / kg body weight / day, or on the one hand about 0.5 mg to about 7 g / patient / day, are useful for the treatment of the above indicated symptoms. For example, the inflammation can be effectively administered by administering about 0.01 to about 50 mg / kg body weight / day or on the one hand about 0.5 mg to about 3.5 g / patient / day, preferably 2.5 mg to 1 g / patient / day. It can be cured.

The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a human oral dosage form may contain 0.5 mg to 5 g of an effective agent combined with a suitable and convenient amount of carrier material, which may vary from about 5 to about 95% of the total composition. A unit dosage form generally contains about 1 mg to about 500 mg of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg. Will contain.

However, the specific dose level for any particular patient depends on a variety of factors including age, weight, general health, sex, diet, time of administration, route of administration, rate of secretion, drug combination and severity of the particular disease being treated. Of course it is.

The invention is now described in more detail with reference to the following non-limiting examples.

Synthesis of Compound

Example 1. 4- [2- (3,5-dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid (1)

a) methyl 3,5-dimethoxy-4-i-propylbenzoate

The compound was obtained using the method disclosed in WO 01/42231. ¹ HNMR (CDCl ₃ , ppm): δ 1.32 (d, J = 7.2 Hz, 6H), 3.66 (center line, J = 7.2 Hz, 1H), 3.82 (s, 6H), 3.95 (s, 3H), 7.25 (s, 2H).

b) 3,5-dimethoxy-4-i-propylbenzyl alcohol

Methyl 3,5-dimethoxy-4-i-propylbenzoate in ether (300 mL) under N ₂ at 0 ° C. in a suspension of LiAlH ₄ (95%) (5.00 g, 125 mmol) in anhydrous ether (100 mL). (15.7 g, 90.1 mmol) solution was added. The suspension was stirred at 0 ° C. for 1 hour and then at room temperature for a further 1 hour. The reaction was quenched by the slow addition of saturated aqueous Na ₂ SO ₄ (10 mL) at 0 ° C. The mixture was stirred overnight. The solid was filtered off and the filtrate was evaporated to dryness to afford the desired alcohol (13.8 g, 88% yield) as white crystals. ¹ HNMR (CDCl ₃ , ppm): δ 1.34 (d, J = 7.2 Hz, 6H), 3.65 (center line, J = 7.2 Hz, 1H), 3.88 (s, 6H), 4.70 (s, 2H), 6.62 (s, 2H).

c) 3,5-dimethoxy-4-i-propylbenzyl aldehyde

A mixture of 3,5-dimethoxy-4-i-propylbenzyl alcohol (13.05 g, 62.1 mmol) and pyridinium chlorochromate (33.92 g, 157 mmol) was added in the presence of K ₂ CO ₃ (4.18 g, 30 mmol). Stir in CHCl (100 mL) for 30 minutes. Ether (300 mL) was added to quench the reaction. The mixture was passed through a Florisil short pad and the pad was thoroughly washed with ether. The solvent was evaporated to give 3,5-dimethoxy-4-i-propylbenzyl alcohol (11.89 g, 92% yield) as yellowish crystals. ¹ HNMR (CDCl ₃ , ppm): δ 1.32 (d, J = 7.2 Hz, 6H), 3.68 (seven line, J = 7.2 Hz, 1H), 3.92 (s, 6H), 7.12 (s, 2H), 9.96 (s, 1 H).

d) (3,5-dimethoxy-4-i-propylphenyl) ethene

To a suspension of methyltriphenylphosphonium bromide (6.89 g, 19.3 mmol) in THF (100 mL) was added BuLi (7.7 mL, 2.5 M in hexane, 19.3 mmol) at room temperature under argon. The resulting red solution was stirred for 10 minutes and then 3,5-dimethoxy-4-i-propylbenzyl aldehyde (4.02 g, 19.3 mmol) in THF (20 mL) was added. After 2 hours, the reaction was quenched with water (20 mL). The mixture was extracted with ether (3 x 100 mL). The extract was washed with saturated brine solution (3 × 30 mL) and dried over sodium sulfate. The ether was evaporated and then flash chromatographed with 3% ethyl acetate in hexanes to give pure (3,5-dimethoxy-4-i-propylphenyl) ethene (2.64 g, 66% yield) as a colorless solid. ¹ HNMR (CDCl ₃ , ppm): δ 1.31 (d, J = 7.2 Hz, 6H), 3.61 (folder line, J = 7.1 Hz, 1H), 3.86 (s, 6H), 5.25 (d, J = 11 Hz, 1H), 5.73 (d, J = 17 Hz, 1H), 6.64 (s, 2H), 6.70 (dd, J = 11, 17 Hz, 1H).

e) 4- [2- (3,5-dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid (1)

(3,5-dimethoxy-4-i-propylphenyl) ethene (0.303 g, 1.50 mmol) in DMF (7 mL), 4-bromobenzoic acid (0.269 g, 1.30 mmol), dihydrogen di-μ-chloro Mixture of tetrakis (di-tert-butylphosphinito-κP) dipaladate (0.0625 g, 0.067 mmol), Bu ₄ NI (0.245 g, 0.67 mmol) and K ₂ CO ₃ (0.614 g, 4.40 mmol) Was heated at 140 ° C. under argon. After completion of the reaction (5 hours), the reaction mixture was poured into water (100 mL). It was washed with ether. The aqueous phase was acidified with 6N HCl and extracted with ether (2 × 100 mL). The extract was washed with saturated sodium chloride and then dried over anhydrous Na ₂ SO ₄ . The ether was evaporated to give pure acid 1 (0.345 g, 71% yield). ¹ HNMR (CDCl ₃ , ppm): δ 1.32 (d, J = 7.1 Hz, 6H), 3.63 (folder line, J = 7.1 Hz, 1H), 3.90 (s, 6H), 6.76 (s, 2H), 7.08 (d, J = 17 Hz, 1H), 7.27 (d, J = 17 Hz, 1H), 7.63 (d, J = 8 Hz, 2H), 8.13 (d, J = 8 Hz, 2H).

Example 2. 3- [2- (3,5-dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid (2)

The compound was synthesized in 77% yield from (3,5-dimethoxy-4-i-propylphenyl) ethene and 3-bromobenzoic acid in the same manner as described in the preparation of 1. ¹ HNMR (CDCl ₃ , ppm): δ 1.32 (d, J = 7.1 Hz, 6H), 3.63 (folder line, J = 7.1 Hz, 1H), 3.90 (s, 6H), 6.76 (s, 6H), 7.08 (d, J = 17 Hz, 1H), 7.25 (d, J = 17 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H), 8.31 (s, 1H).

Example 3. 4- [2- (3,5-Dihydroxy-4-i-propylphenyl) ethenyl] benzoic acid (6)

A mixture of 4- [2- (3,5-dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid (0.289 g, 0.886 mmol) and pyridine hydrochloride (0.678, 5.9 mmol) was added at 200 ° C. under an argon stream. Heated for 1 hour. The reaction mixture was cooled to room temperature. 2N HCl (10 mL) and ether (50 mL) were added. The organic layer was separated and the aqueous mixture was extracted with ether (2 x 50 mL). The extract was washed with saturated brine and dried over anhydrous Na ₂ SO ₄ . The ether was evaporated and then flash chromatographed with ethyl acetate / hexanes / acetic acid (40/60/1) to give pure acid 6 (0.03 g, 11% yield). ¹ HNMR (DMSO-d ₆ , ppm): δ 1.22 (d, J = 7.0 Hz), 6.49 (s, 2H), 6.90 (d, J = 18 Hz, 1H), 7.19 (d, J = 18 Hz, 1H) , 7.67 (d, J = 8 Hz, 2H), 7.90 (d, J = 8 Hz, 2H), 9.14 (s, 2H).

Example 4. 3- [2- (3,5-Dihydroxy-4-i-propylphenyl) ethenyl] benzoic acid (7)

The material was prepared in 86% yield from 3- [2- (3,5-dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid 2 and pyridine hydrochloride in the same manner as described in Example 3. ¹ HNMR (DMSO-d ₆ , ppm): δ 1.22 (d, J = 7.0 Hz, 6H), 6.48 (s, 2H), 7.03 (d, J = 17 Hz, 1H), 7.12 (d, J = 17 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.7-7.9 (m, 2H), 8.06 (s, 1H), 9.12 (s, 2H).

Example 5. 1- (3,5-dimethoxy-4-i-propylphenyl) -2-phenylethene (19)

a). Diethyl benzylphosphonate

A mixture of benzyl bromide (12 mL, 101 mmol) and triethyl phosphite (25 mL, 146 mmol) was heated overnight at 110-130 ° C. in the presence of Bu ₄ NI (0.05 g). Excess triethyl phosphite was removed at 110 ° C. under reduced pressure. Phosphonate (23 g) was obtained quantitatively as a colorless liquid. ¹ HNMR (CDCl ₃ , ppm): δ 1.28 (t, J = 7.2 Hz, 6H), 3.20 (d, J = 21.9 Hz, 2H), 4.10 (dt, J = 7.2 Hz, 7.2 Hz, 4H), 7.30 (s, 5H).

b). 1- (3,5-dimethoxy-4-i-propylphenyl) -2-phenylethene (19)

To the resulting diethyl benzylphosphonate (11.39 g, 54.7 mmol) solution in THF (100 mL) was added NaH (60% in inorganic oil) (4.68 g, 115 mmol) under N ₂ at 0 ° C. After the addition was complete, the suspension was stirred at 0 ° C. for 1 hour and the 3,5-dimethoxy-4-i-propylbenzyl aldehyde (11.39 g, 54.7 obtained in Example 1 (c) in THF (100 mL) Mmol). The reaction was maintained at 0 ° C. for 1 hour and then at 45-50 ° C. for 5 hours. The reaction was cooled to 0 ° C. The reaction was quenched by the slow addition of water followed by the addition of 2N HCl (75 mL). The mixture was extracted with ether (3 x 200 mL). The extract was dried over anhydrous Na ₂ SO ₄ . The ether was evaporated to afford crude 5- (2-phenylethenyl) -2-i-propyl-1,3-dimethoxy benzene (18.07 g). This was used for the next reaction without further purification. A small amount of crude product was purified by flash chromatography using 10% ethyl acetate in hexanes to give pure product. ¹ HNMR (CDCl ₃ , ppm): δ 1.28 (d, J = 7.0 Hz, 6H), 3.58 (center line, J = 7.0 Hz, 1H), 3.85 (s, 6H), 6.69 (s, 2H), 7.05 (s, 2H), 7.25 (m, 1H), 7.35 (m, 2H), 7.25 (m, H).

Example 6. 5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol (20)

To crude 1- (3,5-dimethoxy-4-i-propylphenyl) -2-phenylethene (18.07 g) in anhydrous CH ₂ Cl ₂ (100 mL) BBr ₃ (5.2 under N ₂ at −78 ° C. Ml, 55 mmol) was added dropwise. After the reaction was stirred at -78 ° C for 1 hour, the temperature was raised to room temperature and the reaction mixture was stirred at room temperature for 2 days. The reaction was quenched by addition of water, and then the pH was adjusted to> 12 by addition of 20% NaOH. The organic layer was removed and the aqueous layer was washed with hexane (2 x 100 mL). The aqueous layer was acidified to pH 1 with 6N HCl and extracted with ether (3 × 200 mL). The organic layer was separated, washed with water (50 mL) and brine (50 mL) and dried over anhydrous Na ₂ SO ₄ . The ether was evaporated to give a red syrup. Recrystallization with chloroform gave 20 (6.92 g) of pure stilbene product as white crystals. The mother liquor was concentrated and the residue was recrystallized once more to give an additional 2.5 g of 20 (total 9.42 g, 67.7% over two steps). ¹ HNMR (CDCl ₃ , ppm): δ 1.38 (d, J = 7.3 Hz, 6H), 3.46 (single line, J = 7.3 Hz, 1H), 4.80 (s, 2H), 6.50 (s, 2H), 6.92 (d, J = 17.2 Hz, 1H), 6.97 (d, J = 17.2 Hz, 1H), 7.25 (m, 1H), 7.34 (m, 2H), 7.52 (m, 2H).

Example 7. 3-acetoxy-5- (2-phenylethenyl) -2-i-propylphenyl acetate (10)

5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol (1.00 g, 3.93 mmol) and triethylamine (1.5 mL, obtained in Example 11 in dichloromethane (100 mL) 10.8 mmol) was added dropwise acetyl chloride at 0 ° C. The reaction was monitored by TLC. After the reaction was completed (˜30 min) water (50 mL) was added. The organic layer was separated and washed with 2N HCl (30 mL), H ₂ O (50 mL), saturated NaHCO ₃ (50 mL), H ₂ O (50 mL) and brine (50 mL) and dried over anhydrous sodium sulfate. I was. The solution was evaporated and then flash chromatographed with 5% ethyl acetate in hexanes to give 3-acetoxy-5- (2-phenylethenyl) -2-i-propylphenyl acetate (1.32 g, 92%) as a white solid. Obtained. ¹ HNMR (CDCl ₃ , ppm): δ 1.26 (d, J = 7.0 Hz, 6H), 2.35 (s, 6H), 3.08 (center line, J = 7.0 Hz, 1H), 6.98 (d, J = 17.4 Hz , 1H), 7.04 (d, J = 17.4 Hz, 1H), 7.07 (s, 2H), 7.24-7.29 (m, 1H), 7.34-7.38 (m, 2H), 7.45-7.49 (m, 2H).

Example 8. 3-Chloroacetoxy-5- (2-phenylethenyl) -2-i-propylphenyl chloroacetate (11)

This material was obtained in 72% yield from 5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol and anhydrous chloroacetic acid obtained in Example 11 by the same procedure as described in Example 12. Synthesized. ¹ HNMR (CDCl ₃ , ppm): δ 1.30 (d, J = 7.0 Hz, 6H), 3.08 (center line, J = 7.0 Hz, 1H), 4.39 (s, 4H), 6.96 (d, J = 17 Hz, 1H), 7.14 (d, J = 17 Hz, 1H), 7.17 (s, 2H), 7.2-7.5 (m, 5H).

Example 9. 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (4-methoxyphenyl) ethene (12)

a). 3,5-dimethoxy-4-isopropyl benzyl bromide

PBr ₃ (3.0 mL, 31.2 mmol) was added dropwise under nitrogen at 0 ° C. to 3,5-dimethoxy-4-i-propylbenzyl alcohol (12.57 g, 59.8 mmol) in anhydrous ether (100 mL). The reaction was monitored by TLC. After the reaction was completed (˜4 hours), water (180 mL) was added. The organic layer was separated and the aqueous layer was extracted with ether (3 x 50 mL). The extract was washed with water (20 mL), saturated Na ₂ CO ₃ (20 mL), water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate. The solution was evaporated to give pure bromide (14.93 g, 91.4%) as a white solid. ¹ HNMR (CDCl ₃ , ppm): δ 1.29 (d, J = 7.1 Hz, 6H), 3.64 (seven line, J = 7.1 Hz, 1H), 3.84 (s, 6H), 4.50 (s, 2H), 6.60 (s, 2H).

b). Diethyl (3,5-dimethoxy-4-i-propylbenzyl) phosphonate

A mixture of 3,5-dimethoxy-4-i-propylbenzyl bromide (5.01 g, 18.3 mmol) and triethyl phosphite (4.7 mL, 27.4 mmol) was charged at 110-130 ° C. in the presence of Bu ₄ NI (0.05 g). Heated overnight at. Excess triethyl phosphite was removed at 110 ° C. under reduced pressure to give phosphonate (5.58 g, 92%). ¹ HNMR (CDCl ₃ , ppm): δ 1.27 (d, J = 7.1 Hz, 6H), 1.29 (t, J = 7.0 Hz, 6H), 3.12 (d, J = 21.5 Hz, 2H), 3.4-3.7 ( m, 1H), 3.80 (s, 6H), 4.06 (dt, J = 7.1, 7.1 Hz, 4H), 6.50 (d, J = 2.6 Hz, 2H).

c). 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (4-methoxyphenyl) ethene (12)

The material was prepared in 63% yield from diethyl (3,5-dimethoxy-4-i-propylbenzyl) phosphonate and 4-anisaldehyde following the same procedure as described in Example 5 (b). ¹ HNMR (CDCl ₃ , ppm): δ 1.31 (d, J = 7.1 Hz, 6H), 3.51-3.74 (m, 1H), 3.86 (s, 3H), 3.91 (s, 6H), 6.71 (s, 2H ), 6.84-7.09 (m, 4H), 7.39-7.60 (m, 2H).

Example 10. 5- [2- (4-hydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol (13)

The material was prepared in 30% yield from 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (4-methoxyphenyl) ethene and pyridine hydrochloride in the same manner as described in Example 3. It was. ¹ HNMR (DMSO-d ₆ , ppm): δ 1.22 (d, J = 7.0 Hz, 6H), 3.41 (m, 1H), 6.40 (s, 2H), 6.73 (d, J = 6.3 Hz, 4H), 7.33 (s, 1 H), 7.41 (s, 1 H), 8.98 (s, 2 H), 9.51 (s, 1 H).

Example 11. 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3,5-dimethoxyphenyl) ethene (14)

The material was prepared from diethyl (3,5-dimethoxy-4-i-propylbenzyl) phosphonate and 3,5-dimethoxybenzaldehyde following the same procedure as described in Example 5 (b).

Example 12. 5- [2- (3,5-dihydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol (15)

The material was prepared from 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3,5-dimethoxyphenyl) ethene and BBr ₃ by the same procedure as described in Example 11.

Example 13. 1- (4-Bromo-3,5-dimethoxyphenyl) -2-phenylethene (21)

a) methyl 4-bromo-3,5-dimethoxybenzoate

The material was synthesized in 95% yield from 4-bromo-3,5-dihydroxybenzoic acid and Me ₂ SO ₄ by the same method as described in Example 1 (a). ¹ HNMR (CDCl ₃ , ppm): δ 3.96 (s, 3H), 3.99 (s, 6H), 7.28 (s, 2H).

b). 4-bromo-3,5-dimethoxybenzyl alcohol

The material was prepared in 85% yield from the methyl 4-bromo-3,5-dimethoxybenzoate obtained above by the same method as described in Example 1 (b). ¹ HNMR (CDCl ₃ , ppm): δ 1.95 (s, 1H), 3.93 (s, 6H), 4.69 (s, 2H), 6.61 (s, 2H).

c). 4-bromo-3,5-dimethoxybenzaldehyde

The material was prepared in 75% yield from 4-bromo-3,5-dimethoxybenzyl alcohol by the same method as described in Example 1 (c). ¹ HNMR (CDCl ₃ , ppm): δ 4.02 (s, 6H), 7.11 (s, 2H), 9.97 (s, 1H).

d). 1- (4-bromo-3,5-dimethoxyphenyl) -2-phenylethene (21)

The material was prepared in 70% yield from 4-bromo-3,5-dimethoxybenzyl aldehyde and diethyl benzylphosphonate by the same method as described in Example 5 (b). ¹ HNMR (CDCl ₃ , ppm): δ 3.96 (s, 6H), 6.72 (s, 2H), 7.06 (d, J = 17 Hz, 1H), 7.11 (d, J = 17 Hz, 1H), 7.28 (m, 1H), 7.37 (m, 2H), 7.55 (m, 2H).

Example 14. 2-Bromo-5- (2-phenylethenyl) -1,3-benzenediol (22)

The material was prepared in 90% yield from 1- (4-bromo-3,5-dimethoxyphenyl) -2-phenylethene (21) and BBr ₃ by the same method as described in Example 6. ¹ HNMR (CDCl ₃ , ppm): δ 5.39 (s, 2H), 6.81 (s, 2H), 7.06 (d, J = 17 Hz, 1H), 7.11 (d, J = 17 Hz, 1H), 7.28 (m, 1H), 7.37 (m, 2H), 7.55 (m, 2H).

Example 15. 1- [2,5-dimethoxy-4- (2-phenylethenyl)] phenyl-1-phenylmethanol (16)

BuLi (0.3 mL, 2.5 in hexanes at -78 ° C. in anhydrous THF (1- (4-bromo-3,5-dimethoxyphenyl) -2-phenylethene (0.2185 g, 0.6845 mmol) solution in 10 mL0) M, 0.7530 mmol) was added 1 hour after the addition of benzylaldehyde (0.07 mL, 0.69 mmol) The reaction mixture was stirred for an additional 4 hours at −78 ° C. and then water (12 mL) was added. The reaction was quenched by addition, it was extracted with ether (3 × 20 mL) The extracts were combined and dried over anhydrous Na ₂ SO _{4 The} solvent was extracted and then flash chromatographed with 5% ethyl acetate in hexanes to give a yellow solid. Pure 16 (0.203, 86% yield) as ¹ HNMR (CDCl ₃ , ppm): δ 3.88 (s, 6H), 4.26 (d, J = 5.6 Hz, 1H), 6.40 (br, 1H), 6.79 (s, 2 H), 7.12 (s, 2 H), 7.2-7.6 (m, 10 H).

Example 16. 2,5-dimethoxy-4- (2-phenylethenyl) benzaldehyde (17)

The compound was obtained in 38% yield from 1- (4-bromo-3,5-dimethoxyphenyl) -2-phenylethene, BuLi and N, N-dimethylformamide by the same method as described in Example 15. Synthesized. ¹ HNMR (CDCl ₃ , ppm): δ 3.94 (s, 3H), 4.00 (s, 3H), 6.75 (s, 2H), 7.14 (s, 2H), 7.3-7.5 (m, 5H), 10.52 (s , 1H).

Example 17. 1- (3,5-dimethoxy-4-ethylphenyl) -2-phenylethene (23)

To a solution of 1- (4-bromo-3,5-dimethoxyphenyl) -2-phenylethene (0.53 g, 1.7 mmol) in THF (10 mL) t-butyl Li (1.1 mL, THF 1M) was added. After completion of the addition, the solution was slowly heated to reflux for 30 minutes and then cooled to -78 ° C. Ethyl iodide (1.2 equiv, 0.27 mL) was added to the solution. After the reaction was completed, water (10 mL) was added. THF was evaporated and the mixture was extracted with CH ₂ Cl ₂ (3 × 5 mL). The extracts were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated and then flash chromatographed using 20% ether in hexanes to give 1,3-dimethoxy-2-ethyl-5- (2-phenylethenyl) benzene in 70% yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.12 (t, J = 7.2 Hz, 6H), 2.70 (q, J = 7.2 Hz, 2H), 3.91 (s, 6H), 6.74 (s, 2H), 7.07 ( s, 2H), 7.26 (m, 1H), 7.36 (m, 2H '), 7.52 (m, 2H).

Example 18. 2-ethyl-5- (2-phenylethenyl) -1,3-benzenediol (24)

The material was synthesized in 91% yield from 1- (3,5-dimethoxy-4-ethylphenyl) -2-phenylethene and BBr ₃ by the same method as described in Example 6. ¹ HNMR (CDCl ₃ , ppm): δ 1.22 (t, J = 7.5 Hz, 6H), 2.70 (q, J = 7.5 Hz, 2H), 4.81 (s, 2H), 6.60 (s, 2H), 7.00 ( s, 2H), 7.26 (m, 1H), 7.36 (m, 2H), 7.52 (m, 2H).

Example 19. 1- (3,5-dimethoxy-4-n-tetradecanylphenyl) -2-phenylethene (25)

The material was prepared from 2-bromo-1,3-dimethoxy-5- (2-phenylethenyl) benzene and 1-bromo-n-tetradecane by the same method as described in Example 15. ¹ HNMR (CDCl ₃ , ppm): δ 0.91 (m, 6H), 1.29 (m, 22H), 2.65 (m, 2H), 3.90 (s, 6H), 6.73 (s, 2H), 7.10 (s, 2H ), 7.26 (m, 1 H), 7.36 (m, 2 H), 7.52 (m, 2 H).

Example 20. 5- (2-phenylethenyl) -2-n-tetradecanyl-1,3-benzenediol (26)

The material was synthesized from 1- (3,5-dimethoxy-4-n-tetradecanylphenyl) -2-phenylethene and BBr ₃ by the same method as described in Example 6. ¹ HNMR (CDCl ₃ , ppm): δ 0.95 (m, 6H), 1.30 (m, 22H), 2.65 (m, 2H), 4.80 (s, 2H), 6.60 (s, 2H), 7.00 (s, 2H ), 7.26 (m, 1 H), 7.36 (m, 2 H), 7.52 (m, 2 H).

Example 21. 2- (3,5-dimethoxy-4-i-propylphenyl) -1- (2-fluorophenyl) ethene (27)

To a solution of diethyl (3,5-dimethoxy-4-i-propylbenzyl) phosphonate (0.50 g, 1.5 mmol) in THF (10 mL) under Na ₂ (60% in inorganic oil) (0.14 g, 3.5 mmol) was added. After the addition was complete, the suspension was stirred at 0 ° C. for 1 hour and then 2-fluorobenzaldehyde (0.2 mL, 1.9 mmol) in THF (10 mL) was added. The reaction was kept at 0 ° C. for 1 hour and then at 50 ° C. for 5 hours. The reaction was cooled to 0 ° C. Water (5 mL) was added slowly to quench the reaction followed by 2N HCl (8 mL). The mixture was extracted with ether (3 x 20 mL). The extract was dried over anhydrous Na ₂ SO ₄ . The ether was evaporated and then flash chromatographed using 5% ethyl acetate in hexane as eluent to give 2- (3,5-dimethoxy-4-i-propylphenyl) -1- (2-fluorophenyl as yellow crystals. ) Ethene (1) (0.31 g, 68%) was obtained. ¹ HNMR (CDCl ₃ , ppm): δ 1.34 (d, J = 7.1 Hz, 6H), 3.60 (folder line, J = 7.1 Hz, 1H), 3.89 (s, 6H), 6.74 (s, 2H), 7.0 -7.2 (m, 5H), 7.4-7.6 (m, 1H).

Example 22. 1- (3,5-Dimethoxy-4-i-propylphenyl) -2- (3-fluorophenyl) ethene (28)

The material was prepared from diethyl (3,5-dimethoxy-4-i-propylbenzyl) phosphonate and 3-fluorobenzaldehyde in the same manner as described in Example 21.

Example 23. 1- (3,5-Dimethoxy-4-i-propylphenyl) -2- (4-fluorophenyl) ethene (29)

The material was prepared from diethyl (3,5-dimethoxy-4-i-propylbenzyl) phosphonate and 4-fluorobenzaldehyde in the same procedure as described in Example 21.

Example 24. 2- (3,5-difluorophenyl) -1- (3,5-dimethoxy-4-i-propylphenyl) ethene (30)

The material was prepared in 27% yield from (3,5-dimethoxy-4-i-propylbenzyl) phosphonate and 3,5-difluorobenzaldehyde in the same manner as described in Example 21. ¹ HNMR (CDCl ₃ , ppm): δ 1.32 (d, J = 7.0 Hz, 6H), 3.66 (folder line, J = 7.0 Hz, 1H), 3.90 (s, 6H), 6.72 (s, 2H), 6.8 -7.2 (m, 5 H).

Example 25. 1- (2,4-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethene (31)

(3,5-dimethoxy-4-i-propylphenyl) ethene

To a suspension of methyltriphenylphosphonium bromide (6.89 g, 19.3 mmol) in THF (100 mL) was added BuLi (7.7 mL, 2.5M in hexane, 19.3 mmol) at room temperature under argon. The resulting red solution was stirred for 10 minutes, and then 3,5-dimethoxy-4-i-propylbenzylaldehyde (4.02 g, 19.3 mmol) obtained above in THF (20 mL) was added. After 2 hours, the reaction was quenched with water (20 mL). The mixture was extracted with ether (3 x 100 mL). The extract was washed with saturated brine solution (3 × 30 mL) and dried over sodium sulfate. Ethe was evaporated and then flash chromatographed with 3% ethyl acetate in hexanes to give pure (3,5-dimethoxy-4-i-propylphenyl) ethene (2.64 g, 66% yield) as a colorless solid. ¹ HNMR (CDCl ₃ , ppm): δ 1.31 (d, J = 7.1 Hz, 6H), 3.61 (folder line, J = 7.1 Hz, 1H), 3.86 (s, 6H), 5.25 (d, J = 11 Hz, 1H), 5.73 (d, J = 17 Hz, 1H), 6.64 (s, 2H), 6.70 (dd, J = 11, 17 Hz, 1H).

(3,5-dimethoxy-4-i-propylphenyl) ethene (0.649 g, 3.15 mmol), 1-bromo-2,4-difluorobenzene (1.23 g, 6.37 mmol) in DMF (10 mL) , Dihydrogen di-μ-chlorotetrakis (di-tert-butylphosphinito-κP) dipaladate (0.1409 g, 0.151 mmol), Bu ₄ NI (0.582 g, 1.58 mmol) and K ₂ CO ₃ ( 1.45 g, 10.5 mmol) was heated at 140 ° C. under argon. After the reaction was completed (6 hours), the reaction mixture was poured into water (10 mL). The aqueous solution was acidified with 2N HCl and extracted with ether (2 × 50 mL). The extract was washed with saturated sodium chloride and then dried over anhydrous Na ₂ SO ₄ . The ether was evaporated and then flash chromatographed with 2% ethyl acetate in hexanes to give 1- (2,4-difluorophenyl) -2- (3,5-dimethoxy-4-i- as yellowish crystals. Propylphenyl) ethene 31 was obtained quantitatively. ¹ HNMR (CDCl ₃ , ppm): δ 1.32 (d, J = 7.1 Hz, 6H), 3.63 (folder line, J = 7.1 Hz, 1H), 3.90 (s, 6H), 6.76 (s, 2H), 7.08 (d, J = 17 Hz, 1H), 7.27 (d, J = 17 Hz, 1H), 7.63 (d, J = 8 Hz, 2H), 8.13 (d, J = 8 Hz, 2H).

Example 26. 1- (2,6-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethene (32)

The compound was quantitatively synthesized from (3,5-dimethoxy-4-i-propylphenyl) ethene and 1-bromo-2,6-difluorobenzene in the same procedure as described for the preparation of 31. ¹ HNMR (CDCl ₃ , ppm): δ 1.32 (d, J = 7.1 Hz, 6H), 3.62 (fold line, J = 7.1 Hz, 1H), 3.90 (s, 6H), 6.73 (s, 2H), 6.8 -7.2 (m, 4H), 7.41 (d, J = 16.6 Hz, 1H).

Example 27. 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (2,4,6-trifluorophenyl) ethene (33)

The compound was synthesized in 58% yield from (3,5-dimethoxy-4-i-propylphenyl) ethene and 1-bromo-2,4,6-trifluorobenzene in the same procedure as described for the preparation of 31. It was. ¹ HNMR (CDCl ₃ , ppm): δ 1.32 (d, J = 7.1 Hz, 6H), 3.62 (fold line, J = 7.1 Hz, 1H), 3.89 (s, 6H), 6.73 (s, 2H), 6.79 -7.55 (m, 4 H).

Example 28. 1- (3,5-Dimethoxy-4-i-propylphenyl) -2- (2,3,4,5,6-pentafluorophenyl) ethene (34)

The compound was synthesized from (3,5-dimethoxy-4-i-propylphenyl) ethene and 1-bromo-2,3,4,5,6-pentafluorobenzene in the same procedure as described for the preparation of 31 It was.

Example 29. 5- [2- (2-fluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (37)

Of 2- (3,5-dimethoxy-4-i-propylphenyl) -1- (2-fluorophenyl) ethene (27) (0.30 g, 1.03 mmol) and pyridine hydrochloride (0.72 g, 6.2 mmol) The mixture was heated at 200 ° C. under an argon stream for 4 hours. The reaction mixture was cooled to room temperature. 2N HCl (10 mL) and ether (15 mL) were added. The organic layer was separated and the aqueous layer was extracted with ether (3 x 10 mL). The extract was dried over anhydrous Na ₂ SO ₄ . The ether was evaporated and flash chromatographed using 15% ethyl acetate in hexane to give pure 5- [2- (2-fluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (as a gray solid). 37) (0.269 g, 95% yield). ¹ HNMR (CDCl ₃ , ppm): δ 1.41 (d, J = 7.2 Hz, 6H), 3.51 (folder line, J = 7.2 Hz, 1H), 5.01 (b, 2H), 6.56 (s, 2H), 6.98 (d, J = 17.6 Hz, 1H), 7.0-7.3 (m, 4H), 7.60 (ddd, J = 7.5, 7.5, 2.2 Hz, 1H).

Example 30. 5- [2- (3-fluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol (38)

The material was prepared from 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3-fluorophenyl) ethene (28) and pyridine hydrochloride in the same procedure as described in Example 34. . ¹ HNMR (CDCl ₃ , ppm): δ 1.41 (d, 7.2 Hz, 6H), 3.49 (fold line, J = 7.2 Hz, 1H), 6.53 (s, 2H), 6.9-7.5 (m, 6H).

Example 31. 5- [2- (4-fluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol (39)

The material was prepared from 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (4-fluorophenyl) ethene (29) and pyridine hydrochloride in the same procedure as described in Example 34. (38% yield over 2 steps). ¹ HNMR (CDCl ₃ , ppm): δ 1.41 (d, 7.2 Hz, 6H), 3.48 (fold line, J = 7.2 Hz, 1H), 6.52 (s, 2H), 6.81 (d, J = 17 Hz, 1H) , 7.00 (d, J = 17 Hz, 1H), 7.0-7.2 (m, 2H), 7.4-7.6 (m, 2H); ¹ HNMR (DMSO-d ₆ , ppm): δ 1.22 (d, J = 7.1 Hz, 6H), 3.35 (folder line, J = 7.1 Hz, 1H), 6.45 (s, 2H), 6.81 (d, J = 16.7 Hz, 1H), 6.99 (d, J = 16.7 Hz, 1H), 7.17 (dd, J = 8.8, 8.8 Hz, 2H), 7.61 (dd, J = 8.8 Hz, 5.6 Hz, 2H), 9.05 (s , 2H).

Example 32. 5- [2- (3,5-difluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol (40)

The material was 70% from 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3,5-difluorophenyl) ethene and pyridine hydrochloride in the same procedure as described in Example 34. Prepared in yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.40 (d, 7.2 Hz, 6H), 3.56 (fold line, J = 7.2 Hz, 1H), 4.90 (s, 2H), 6.52 (s, 2H), 6.2-7.1 (m, 5 H).

Example 33. 5- [2- (2,4-difluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (41)

The material was 44% from 1- (2,4-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethene and pyridine hydrochloride in the same manner as described in Example 34. Prepared in yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.41 (d, 7.1 Hz, 6H), 3.49 (fold line, J = 7.1 Hz, 1H), 4.78 (br, 2H), 6.54 (s, 2H), 6.69-7.02 (m, 3H), 7.13 (d, J = 16 Hz, 1H), 7.41-7.75 (m, 1H).

Example 34. 5- [2- (2,6-fluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (42)

The material was 29% from 1- (2,6-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethene and pyridine hydrochloride in the same manner as described in Example 34. Prepared in yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.42 (d, 7.1 Hz, 6H), 3.50 (fold line, J = 7.1 Hz, 1H), 4.77 (br, 2H), 6.57 (s, 2H), 6.8-7.4 (m, 5 H).

Example 35. 2-i-propyl-5- [2- (2,4,6-trifluorophenyl) ethenyl] -1,3-benzenediol (43)

The material was obtained from 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (2,4,6-trifluorophenyl) ethene and pyridine hydrochloride in the same manner as described in Example 29. Prepared in 14% yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.42 (d, 7.1 Hz, 6H), 3.50 (fold line, J = 7.1 Hz, 1H), 4.77 (br, 2H), 6.55 (s, 2H), 6.59-7.24 (m, 4 H).

Example 36. 5- [2- (2,3,4,5,6-pentafluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (44)

The material was converted to 1- (2,3,4,5,6-pentafluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethene and in the same manner as described in Example 34. Prepared from pyridine hydrochloride in 21% yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.40 (d, 7.2 Hz, 6H), 3.53 (d, J = 7.2 Hz, 6H), 4.91 (s, 2H), 6.55 (s, 2H), 6.86 (d, J = 17 Hz, 1H), 7.28 (d, J = 17 Hz, 1H).

Standard pharmacological procedures, fully described in the Examples below, show that the compounds of the present invention inhibit cell migration, T-cell, keratinocyte proliferation induced by leukotriene B4 and inhibit IFN-γ secretion and VEGF expression in vitro. But also inhibits TNF-α and edema in vivo.

Example 37. Biological Activity of Novel Compounds

Assays for the following biological activities are well established and known in the art and provide a brief description herein for clarity.

(a) Effects on proliferation and IFN- [gamma] production of human peripheral blood mononuclear cells (PBMCs) stimulated by phytochemagglutinin (PHA)

Experiment:

PBMCs were incubated with PHA and incubated with appropriate concentrations of compounds or solvents, or with media alone using standard cell culture techniques. MTT assay was performed after 48 hours of incubation. Supernatants were harvested 48 hours after incubation and levels of IFN-γ were analyzed by ELISA.

result:

5- [2- (4-hydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol (13) of the present invention has an IC ₅₀ of 2.97 for human PBMC proliferation whereas resveratrol is> Had an IC ₅₀ of ₅₀ . Compound 13 is 20 times more potent in inhibiting PBMC proliferation (Table 1). Similarly, compound 13 is at least 15 times more potent than resveratrol in inhibiting IFN- [gamma] production (Table 2). Similarly, the three fluorinated compounds 37, 38 and 39 had an IC ₅₀ of <10 μM while the IC ₅₀ of resveratrol was> 50 μM, the highest concentration tested. The fluorinated compounds have better activity than resveratrol and are> 5 times more potent in inhibiting PBMC proliferation (Table 1). Similarly, IC ₅₀ value of resveratrol is the three high and about 9 times higher than the IC ₅₀ value of the fluorinated compound, which is more than 9 times that of resveratrol in the inhibition of the fluorinated compound to produce IFN-γ by human PBMC more potent Indicates that there is (Table 2).

TABLE 1

Effects of New Compounds and Resveratrol on Human PBMC Proliferation compound IC ₅₀ (μM) 13 2.97 37 5.62 38 9.91 39 7.36 Resveratrol > 50

TABLE 2

Effect of Novel Compounds and Resveratrol on IFN-γ Production by Human PBMCs compound INFγ IC ₅₀ (μM) 13 2.55 37 3.80 38 4.29 39 4.16 Resveratrol 39.2

(b). Effect on Human Keratinocyte Proliferation

Human keratinocytes were cultured in the presence of IFN-γ and the appropriate concentration of drug or vehicle. MTT assay was performed after 48 hours of incubation.

result:

Compound 13>, and compared to the IC ₅₀ of 50 resveratrol had an IC ₅₀ of 4.3 μM, which refers to a compound that is 13 10 times more potent than resveratrol (Table 3).

TABLE 3

Effects of New Compound 13 and Resveratrol on Human Keratinocyte Proliferation compound IC ₅₀ (μM) 13 4.3 Resveratrol > 50

(c) Effect on the migration of human leukocytes (WBC) induced by leukotriene B4

Experiment:

WBC collected from the donor was mixed with an equal volume of 3% dextran (in 0.15 M NaCl). Erythrocytes were removed by sedimentation (45 min, room temperature). Any remaining erythrocytes in plasma were removed by adding 150 mM Tris-NH ₄ Cl. Leukocyte-rich plasma was washed twice with Hank's balanced salt solution containing 20 mM HEPES. WBCs were then transferred to RPMI-1640 medium and the density was adjusted to 5 x 10 ⁷ cells / ml. WBC migration was measured using an agarose plate analysis system (Nelson et al. 1978). Briefly, 0.8% agarose solution was prepared using complete RPMI-1640 cell culture medium. About 3.5 ml of the agarose solution was transferred to a glass slide and then coagulated. Once the agarose had solidified, wells were formed on the slide in a 3 × 6 arrangement (Ø2 mm, well-to-well distance 3 mm). LTB4 was dissolved at 10 ⁴ ng / ml in absolute ethanol and further diluted to 10 ng / ml with RPMI-1640 medium for testing. Compound 39 was dissolved in DMSO and diluted to 10 ³ μg / ml with RPMI-1640 and tested at the following concentrations: 100, 10, 1, 0.1 and 0.01 μg / ml. 10 μl of cell suspension with different concentrations of compound 39 were added to each well of the center row of three rows of wells. Equal volumes of LTB ₄ or the medium in RPMI-1640 medium alone were added to the wells of the other rows and used as controls. After 5 hours incubation (5% CO ₂ , 37 ° C.), the test slides were fixed with 100% methanol (30 min) and dried at 4 ° C. (overnight). The slide was then examined under a microscope. The migration index was defined as the mean distance of the mean distance / voluntary movement of cells towards positive LTB ₄ wells. Percent migration was compared between treated and non-drug controls. The dose-effect relationship was determined by plotting the concentration versus percent chemotaxis for IC ₅₀ values.

result:

Compound 39 inhibited the migration of WBC towards LTB ₄ in a dose-dependent manner (Table 4).

TABLE 4

Effect of Compound 39 on Human Leukocyte Migration Toward LTB ₄ Concentration (μM) move % 40 13.07 ± 5.8 8 58.46 ± 4.3 1.6 83.85 ± 15.9 0.32 88.46 ± 18.6 0 100

conclusion:

Compound 39 showed potent inhibitory activity against WBC migration induced by leukotriene B4, a mediator that plays an important role in inflammation, including autoimmune responses.

(d) Effect on vascular endothelial growth factor (VEGF) protein expression

Experiment:

Compound 39 was dissolved in DMSO, diluted to 10 ³ μg / ml with keratinocyte-serum-ratio containing medium (KC-SFM), further diluted with culture medium, and the following concentrations ie 10, 1, 0.1 and 0.01 Test at μg / ml. Main cultures of keratinocytes were obtained from commercial sources and maintained at a cell density of 10 ⁶ / ml using KC-SFM. In the test, cells were cultured in 24-well plates and first incubated in 5% CO ₂ at 37 ° C. for 4 hours, followed by rhTGF-α (final concentration 100 ng / ml) and different concentrations (0.01 to 10 μg / ml). Treated with test compound. Medium without test compound was a negative control. Culture supernatants from each well were incubated for an additional 24 hours before harvesting separately and centrifugation at 2000 rpm for 5 minutes to determine VEGF concentrations. The VEGF concentration in the supernatant in each well was calculated based on the measurements taken using the ELISA kit according to the manufacturer's instructions.

result:

Compound 39 showed a dose dependent effect on VEGF concentration in the cell supernatant of keratinocytes induced by rhTGF-α after 24 hours treatment. When the concentration of Compound 39 was increased to 40 M, the effect was substantially increased and the protein concentration was reduced by 100% (Table 5).

TABLE 5

Effect of Compound 39 on VEGF Expression in Human Keratinocytes Induced by rhTGF-α Concentration (μM) VEGF (pg / ml) 40 0 ± 0 8 33.6 ± 1.8 1.6 34.4 ± 2.0 0 38.9 ± 2.8

conclusion:

Compound 39 had a significant inhibitory effect on VEGF expression in human keratinocytes.

(e) In vivo efficacy in endotoxin mouse model

Experiment:

Test compounds were formulated by dissolving in 50% PEG-400 in water. Female Balb / c mice (-20 g) were first inoculated separately intraperitoneally (IP) with 25 mg / kg of each test compound, followed by injecting 40 mg / kg of lipopolysaccharide (LPS) 30 minutes later. . One drug infusion with test compound 12.5 mg / kg was performed simultaneously with LPS inoculation followed by two consecutive infusions at 30 minute intervals. The positive control of dexamethasone started at 0.4 mg / kg in a similar manner and then administered 0.2 mg / kg in three additional injections. Mice were killed and blood collected by cardiac puncture 150 min after LPS inoculation. Serum TNF-α levels were measured by ELISA. Each test group included 6 mice. Groups of mice injected with vehicle only were used as negative controls.

result:

Compounds 37 and 39 significantly reduced (P <0.05) TNF-α levels in mouse blood induced by LPS (Table 6).

TABLE 6

Effect of New Compounds 37 and 39 on TNF-α Levels Induced by LPS in Mouse Models compound TNF-α (pg / ml) P value 37 638.9 ± 273.0 0.03 39 601.6 ± 211.9 0.01 carrier 1126.6 ± 396.4 Dexamethasone 281.3 ± 67.2 0.0004

P-value calculated by the Student's t test (unpaired, 2-tailed)

conclusion:

Compounds 37 and 39, which are fluorinated compounds, significantly reduced the levels of TNF-α, which modulates broad activity in mice, which reduced salt response in animals.

(f) Efficacy on TPA induced edema

Experiment:

Three typical compounds, 5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol as previously reported, a closely related stilbene derivative (WO 0142231), and the novel invention Compound 39, a compound, was analyzed for edema on 10-12 week old female mice (Balb / c) using 0.01% calcitriol (commercial standard) as a positive control. Phorbol-12-myristate-13-acetate (TPA) was used as edema inducer. Both TPA and test compounds were dissolved in 100% ethanol and 20 μl applied to the right ear of mice (6 mice per group). The TPA concentration used was 0.01% (w / v). Ear thickness was measured 6 hours after TPA treatment to determine whether edema was reduced. Repetitive groups of TPA treated mice in each experiment were treated with 5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol, calcitriol, compound 39 or just ethanol and ear thickness The level of inhibition was obtained by expressing the difference between the thickness of the measured and treated ears and the ethanol treated ears in percentage.

result:

Fluorinated compounds significantly reduce edema. The novel compound 39 of the present invention wherein one of the H atoms of stilbene 5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol, as reported above, is substituted with F, inhibits edema inhibition at 8% to 85. Inhibition of calcitriol was 31% while decreasing to%, demonstrating the surprisingly high level of activity of the novel compound 39 of the invention.

TABLE 6

Anti-inflammatory Activity of Stilbene Compounds After Single Topical Administration in TPA-Induced Ear Edema Model process Edema Suppression% TPA (0.01%) + 5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol (0.3%) 8.0 TPA (0.01%) + Compound 39 (0.3%) 85.2 TPA (0.01%) + calcitriol (0.01%) 31.2

Claims (29)

A compound of formula (I) or a salt thereof Formula I Where R ¹ is selected from the group consisting of unsubstituted or substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl and aralkyl groups, halo and COR ⁹ ; R ² and R ³ are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl and acyl; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are not H at the same time and independently H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl and aralkyl groups, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , _wherein n is 0 to 2, OR ¹² , a cyclic and heterocyclic group ; Provided that when R ¹ is an unsaturated group consisting of one to three isoprene unit (s), R ⁶ is not a hydroxy or alkoxy group; R ⁹ is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl and aralkyl, and NR ¹⁰ R ¹¹ and OR ¹⁰ ; R ¹⁰ and R ¹¹ are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl and aralkyl; R ¹² is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl and acyl; The arrangement of the double bonds of the above formula (I) is E or Z. The method of claim 1, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl and aralkyl groups, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , _wherein n is 0 to 2, OR ¹² , a cyclic and heterocyclic group, provided that R ⁴ , At least one of R ⁵ , R ⁶ , R ⁷ and R ⁸ is F; The method of claim 1, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of H, COR ⁹ and OR ¹² , provided that at least one of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is COR ⁹ phosphorus compound. The method of claim 3, wherein R ² and R ³ are independently selected from the group consisting of H, unsubstituted or substituted alkyl and acyl. The method of claim 4, wherein R ² and R ³ are independently selected from the group consisting of H, methyl and acetate. The method of claim 2, R ¹ is selected from unsubstituted or substituted alkyl having 1 to 14 carbon atoms; R ² and R ³ are each independently selected from the group consisting of H, unsubstituted or substituted alkyl and acyl. The method of claim 6, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of H and F, provided that at least one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is F. The method of claim 6, R ¹ is isopropyl; R ² and R ³ are each independently selected from the group consisting of H, methyl and acetate. The method of claim 1, A compound selected from the group consisting of: 4- [2- (3,5-dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid; 3- [2- (3,5-dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid; 4- [2- (3,5-dihydroxy-4-i-propylphenyl) ethenyl] benzoic acid; 3- [2- (3,5-dihydroxy-4-i-propylphenyl) ethenyl] benzoic acid; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (4-methoxyphenyl) ethane; 5- [2- (4-hydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3,5-dimethoxyphenyl) ethane; 5- [2- (3,5-dihydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 1- [2,5-dimethoxy-4- (2-phenylethenyl) phenyl] -1-phenylmethanol; 2,5-dimethoxy-4- (2-phenylethenyl) benzaldehyde; 1- (3,5-dimethoxy-4-i-propylphenyl) -2-phenylethane; 5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol; 1- (4-bromo-3,5-dimethoxyphenyl) -2-phenylethene; 2-bromo-5- (2-phenylethenyl) -1,3-benzenediol; 1- (3,5-dimethoxy-4-ethylphenyl) -2-phenylethene; 2-ethyl-5- (2-phenylethenyl) -1,3-benzenediol; 2- (3,5-dimethoxy-4-i-propylphenyl) -1- (2-fluorophenyl) ethane; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3-fluorophenyl) ethane; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (4-fluorophenyl) ethane; 2- (3,5-difluorophenyl) -1- (3,5-dimethoxy-4-i-propylphenyl) ethane; 1- (2,4-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethane; 1- (2,6-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethane; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (2,4,6-trifluorophenyl) ethane; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (2,3,4,5,6-pentafluorophenyl) ethane; 5- [2- (2-fluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 5- [2- (3-fluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol; 5- [2- (4-fluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol; 5- [2- (3,5-difluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol; 5- [2- (2,4-difluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 5- [2- (2,6-difluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 2-i-propyl-5- [2- (2,4,6-trifluorophenyl) ethenyl] -1,3-benzenediol; 5- [2- (2,3,4,5,6-pentafluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol. A pharmaceutical composition comprising a compound of formula (I) or a salt thereof and a pharmaceutically acceptable diluent or carrier: Formula I Where R ¹ is selected from the group consisting of unsubstituted or substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl and aralkyl groups, halo and COR ⁹ ; R ² and R ³ are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl and acyl; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are not H at the same time and independently H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl and aralkyl groups, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , _wherein n is 0 to 2, OR ¹² , a cyclic and heterocyclic group ; Provided that when R ¹ is an unsaturated group consisting of one to three isoprene unit (s), R ⁶ is not a hydroxy or alkoxy group; R ⁹ is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl and aralkyl, and NR ¹⁰ R ¹¹ and OR ¹⁰ ; R ¹⁰ and R ¹¹ are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl and aralkyl; R ¹² is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl and acyl; The arrangement of the double bonds of the above formula (I) is E or Z. The method of claim 10, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl and aralkyl groups, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , _wherein n is 0 to 2, OR ¹² , a cyclic and heterocyclic group, provided that R ⁴ , Wherein at least one of R ⁵ , R ⁶ , R ⁷ and R ⁸ is F; The method of claim 10, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of H, COR ⁹ and OR ¹² , provided that at least one of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is COR ⁹ phosphorus composition. The method of claim 12, R ² and R ³ are independently selected from the group consisting of H, unsubstituted or substituted alkyl and acyl. The method of claim 13, R ² and R ³ are independently selected from the group consisting of H, methyl and acetate. The method of claim 11, R ¹ is selected from unsubstituted or substituted alkyl having 1 to 14 carbon atoms; R ² and R ³ are each independently selected from the group consisting of H, unsubstituted or substituted alkyl and acyl. The method of claim 15, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of H and F, provided that at least one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is F. The method of claim 15, R ¹ is isopropyl; R ² and R ³ are each independently selected from the group consisting of H, methyl and acetate. The method of claim 10, Wherein the compound is selected from the group consisting of: 4- [2- (3,5-dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid; 3- [2- (3,5-dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid; 4- [2- (3,5-dihydroxy-4-i-propylphenyl) ethenyl] benzoic acid; 3- [2- (3,5-dihydroxy-4-i-propylphenyl) ethenyl] benzoic acid; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (4-methoxyphenyl) ethane; 5- [2- (4-hydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3,5-dimethoxyphenyl) ethane; 5- [2- (3,5-dihydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 1- [2,5-dimethoxy-4- (2-phenylethenyl) phenyl] -1-phenylmethanol; 2,5-dimethoxy-4- (2-phenylethenyl) benzaldehyde; 1- (3,5-dimethoxy-4-i-propylphenyl) -2-phenylethane; 5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol; 1- (4-bromo-3,5-dimethoxyphenyl) -2-phenylethene; 2-bromo-5- (2-phenylethenyl) -1,3-benzenediol; 1- (3,5-dimethoxy-4-ethylphenyl) -2-phenylethene; 2-ethyl-5- (2-phenylethenyl) -1,3-benzenediol; 2- (3,5-dimethoxy-4-i-propylphenyl) -1- (2-fluorophenyl) ethane; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3-fluorophenyl) ethane; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (4-fluorophenyl) ethane; 2- (3,5-difluorophenyl) -1- (3,5-dimethoxy-4-i-propylphenyl) ethane; 1- (2,4-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethane; 1- (2,6-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethane; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (2,4,6-trifluorophenyl) ethane; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (2,3,4,5,6-pentafluorophenyl) ethane; 5- [2- (2-fluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 5- [2- (3-fluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol; 5- [2- (4-fluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol; 5- [2- (3,5-difluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol; 5- [2- (2,4-difluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 5- [2- (2,6-difluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 2-i-propyl-5- [2- (2,4,6-trifluorophenyl) ethenyl] -1,3-benzenediol; 5- [2- (2,3,4,5,6-pentafluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol. Use of a compound of formula (I) in the manufacture of a medicament for the treatment of a disease, including an immune, inflammatory or autoimmune disease: Formula I Where R ¹ is selected from the group consisting of unsubstituted or substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl and aralkyl groups, halo and COR ⁹ ; R ² and R ³ are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl and acyl; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are not H at the same time and independently H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl and aralkyl groups, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , _wherein n is 0 to 2, OR ¹² , a cyclic and heterocyclic group ; Provided that when R ¹ is an unsaturated group consisting of one to three isoprene unit (s), R ⁶ is not a hydroxy or alkoxy group; R ⁹ is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl and aralkyl, and NR ¹⁰ R ¹¹ and OR ¹⁰ ; R ¹⁰ and R ¹¹ are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl and aralkyl; R ¹² is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl and acyl; The arrangement of the double bonds of the above formula (I) is E or Z. The method of claim 19, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl and aralkyl groups, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , _wherein n is 0 to 2, OR ¹² , a cyclic and heterocyclic group, provided that R ⁴ , At least one of R ⁵ , R ⁶ , R ⁷ and R ⁸ is F; The method of claim 19, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of H, COR ⁹ and OR ¹² , provided that at least one of R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is COR ⁹ person use. The method of claim 21, R ² and R ³ are independently selected from the group consisting of H, unsubstituted or substituted alkyl and acyl. The method of claim 22, R ² and R ³ are independently selected from the group consisting of H, methyl and acetate. The method of claim 20, R ¹ is selected from unsubstituted or substituted alkyl having 1 to 14 carbon atoms; R ² and R ³ are each independently selected from the group consisting of H, unsubstituted or substituted alkyl and acyl. The method of claim 24, R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of H and F, provided that at least one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is F. The method of claim 24, R ¹ is isopropyl; R ² and R ³ are each independently selected from the group consisting of H, methyl and acetate. The method of claim 19, The compound is selected from the group consisting of: 4- [2- (3,5-dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid; 3- [2- (3,5-dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid; 4- [2- (3,5-dihydroxy-4-i-propylphenyl) ethenyl] benzoic acid; 3- [2- (3,5-dihydroxy-4-i-propylphenyl) ethenyl] benzoic acid; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (4-methoxyphenyl) ethane; 5- [2- (4-hydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3,5-dimethoxyphenyl) ethane; 5- [2- (3,5-dihydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 1- [2,5-dimethoxy-4- (2-phenylethenyl) phenyl] -1-phenylmethanol; 2,5-dimethoxy-4- (2-phenylethenyl) benzaldehyde; 1- (3,5-dimethoxy-4-i-propylphenyl) -2-phenylethane; 5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol; 1- (4-bromo-3,5-dimethoxyphenyl) -2-phenylethene; 2-bromo-5- (2-phenylethenyl) -1,3-benzenediol; 1- (3,5-dimethoxy-4-ethylphenyl) -2-phenylethene; 2-ethyl-5- (2-phenylethenyl) -1,3-benzenediol; 2- (3,5-dimethoxy-4-i-propylphenyl) -1- (2-fluorophenyl) ethane; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3-fluorophenyl) ethane; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (4-fluorophenyl) ethane; 2- (3,5-difluorophenyl) -1- (3,5-dimethoxy-4-i-propylphenyl) ethane; 1- (2,4-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethane; 1- (2,6-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethane; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (2,4,6-trifluorophenyl) ethane; 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (2,3,4,5,6-pentafluorophenyl) ethane; 5- [2- (2-fluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 5- [2- (3-fluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol; 5- [2- (4-fluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol; 5- [2- (3,5-difluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol; 5- [2- (2,4-difluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 5- [2- (2,6-difluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol; 2-i-propyl-5- [2- (2,4,6-trifluorophenyl) ethenyl] -1,3-benzenediol; 5- [2- (2,3,4,5,6-pentafluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol. A method of treating a disease in a mammal comprising administering an effective amount of a compound of formula (I) or a salt thereof as defined in claim 1 to a mammal infected with a disease, including an immune, inflammatory or autoimmune disease. A method of treating a disease in a mammal comprising administering to a mammal infected with a disease, including an immune, inflammatory or autoimmune disease, an effective amount of a compound according to any one of claims 2 to 9 or a salt thereof. .