JP2006508930A - Novel bioactive diphenylethene compounds and their therapeutic applications - Google Patents

Abstract

The present invention relates to a novel group of diphenylethene derivatives, pharmaceutically acceptable salts thereof, methods for preparing these compounds, pharmaceutical compositions thereof, and drugs for treating immune, inflammatory and autoimmune diseases. The use of these compounds is provided.

Description

  It is known to those skilled in the art that stilbene derivatives have a wide range of activities and are widely distributed in nature. Due to the range of activities observed in some of the natural as well as synthetic stilbenes, interest in stilbene derivatives has increased. The stilbene derivative, commonly known as resveratrol, 3,5,4'-trihydroxystilbene, has a range of biology, such as mediation of inflammation and chemoprevention of cancer, for both isomers (cis or trans) Functions have been reported (Jang et al., 1997, Science, 275, 218, US6,008,260).

  Substitution at various positions of the two phenyl rings of the basic stilbene structure has one or two substituents on one or both of the phenyl rings of the stilbene structure (Shudo K., 1988, US4723028; Hensley, KL et al., WO99 / 59561, Kunihiro N., 1983, JP58159410; Genji I., 1995, JP07053359 and GB1465661), and those having three or more substituents on the phenyl ring (Koichi, S. et al., 1986, EP0170105; Shozo Y. et al., 1986, JP08337523; and Charpentier B. et al., 1992, WO92 / 19583) are known to those skilled in the art to provide great diversity of compounds. Compounds having other substitutions on the phenyl ring, such as vitamin A (Ney, U.M. et al., 1987, Dermatologica, 175: 93-99) and vitamin D (WO 00/26167) derivatives are known to those skilled in the art. Several documents (WO92 / 16486, WO99 / 40056, WO01 / 95859 and Cushman M. et al., 1992, J. Med. Chem., 35: 2293-2306) include 3,4,5-trimethoxyl stilbene. Derived compounds are disclosed. These compounds exhibit antineoplastic activity and a small degree of activity that modulates cytokines (WO01 / 95859).

  Recently, a group of stilbenes with a unique substitution pattern with two hydroxyl groups at the 3 and 5 positions, or derivatives thereof, and substituents between them have been disclosed. Our pending application has inhibitory activity against kinases, anti-inflammatory activity (WO01 / 42231), effects on T lymphocytes, macrophages, neutrophils and mast cells, and various immune and inflammatory activities The present invention relates to a compound having an effect of regulating (WO02 / 057219). However, when one phenyl group has the above-mentioned unique substitution pattern and the other phenyl group is substituted with a certain range of specific substituents, particularly fluorine atoms, a compound having surprising immunomodulating activity is obtained. It has not been discovered until now. The present invention relates to these novel stilbene compounds, their synthesis, their unexpected activity, pharmaceutical compositions, and their use in the treatment of disorders associated with these activities.

SUMMARY OF THE INVENTION The invention disclosed herein relates to the following compounds of formula I, pharmaceutically acceptable salts thereof, and pharmaceutical compositions of these compounds found to be useful as immunomodulators.

The present invention includes the following novel compounds of general formula I:

[Where:
R ¹ is selected from the group consisting of unsubstituted or substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl groups, halo, or COR ⁹ ;
R ² and R ³ are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or acyl;
R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are not H at the same time, but H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl group, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , n = 0-2, OR ¹² , independently selected from the group consisting of a ring or a heterocyclic group; provided that R ¹ is When it is an unsaturated group comprising 1-3 isoprene units, R ⁶ is not a hydroxy or alkoxy group;
R ⁹ is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl, or NR ¹⁰ R ¹¹ , or OR ¹⁰ ;
R ¹⁰ and R ¹¹ are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl;
R ¹² is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or acyl. ]
In particular, in general formula I:
R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl group, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O ) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , n = 0-2, OR ¹² , independently selected from the group consisting of cyclic or heterocyclic groups, and R ⁴ , R ⁵ , R A novel compound in which one or more of ⁶ , R ⁷ and R ⁸ is F. The configuration of the double bond of the compound of formula I is E or Z.

  Particularly preferred compounds include the following:

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 general formula I as immunomodulators.

  The compounds of the present invention can be synthesized with specific modifications to the general method disclosed in the patent publication WO02 / 057219. The examples shown here are for illustrative purposes only and are not to be considered as limiting the invention. In general, the stilbene structure of the compounds of the invention is synthesized by Wittig olefination (Scheme 1) and Heck reaction (Scheme 2). The corresponding 1,3-benzenediol can be obtained by deprotection reaction.

Scheme 1. Wittig olefination:

Scheme 2. Heck reaction

Scheme 3. Modification

One modification of R ¹ starts from bromostilbene (Scheme 3). The bromide can be converted to other functional groups by reacting with an electrophile after Suzuki coupling or bromo-lithium exchange.

  The compounds utilized in accordance with the present invention have a double bond Z or E configuration, resulting in trans and cis isomers. All of the above isomers and mixtures of cis and trans isomers are intended to be included within the scope of the present invention.

  Pharmaceutically acceptable salts can be prepared for all compounds of the present invention that have functional groups capable of forming salts. Pharmaceutically acceptable salts are formed with inorganic and / or organic acids and bases. Preferred acids include, for example, pharmaceutically acceptable hydrochloric acid, sulfuric acid, nitric acid, benzenesulfonic acid, acetic acid, maleic acid, tartaric acid and the like. In particular, pharmaceutically acceptable salts are preferred when the compounds of the present invention are used as pharmaceuticals, but other compounds may be used, for example, in the synthesis of these compounds or when intended for non-pharmaceutical use. Salts can also be used.

The compounds of the present invention exhibited a range of immunomodulatory activity, which is demonstrated by example in the examples below. Compounds with immunomodulating activity are known to those skilled in the art and are described in many patent and scientific literature. It is generally known and accepted by those skilled in the art that immunomodulatory activity is useful for treating many diseases and conditions in animals, including humans. A medicament comprising a compound (s) having immunomodulatory activity, such as those disclosed herein as an active ingredient, may be used in clinical transplantation (eg, organ transplantation, acute transplantation or xenograft or allograft (burn) )) Rejection; protection from ischemia or reperfusion injury such as ischemia or reperfusion injury caused by organ transplantation, myocardial infarction, stroke or other causes; induction of transplant resistance; arthritis (Rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; inflammatory bowel diseases including ulcerative colitis and Crohn's disease; lupus (systemic lupus erythematosus); T-cell mediated hypersensitivity diseases, including hypersensitization, delayed hypersensitivity, and gluten-sensitive enteropathy (pediatric steatosis); psoriasis; contact dermatitis (including those caused by poison ivy); Hashimoto's thyroid Sjogren's syndrome; autoimmune hyperthyroidism such as Graves'disease;Addison's disease (adrenal autoimmune disease); autoimmune multi-gland disease (also known as autoimmune multi-gland syndrome); autoimmune hair loss; autoimmunity Anemia; vitiligo; autoimmune pituitary function, Gann-Barre syndrome; other autoimmune diseases; glomerulonephritis, serum disease; urticaria; respiratory allergy (asthma, hay fever, allergic rhinitis) or skin allergy Scleracierma; mushroom-like mycosis; acute inflammatory response (such as acute dyspnea syndrome and ischemia / reperfusion injury); dermatomyositis; alopecia areata; chronic photodermatitis; eczema; Those skilled in the art are useful for the treatment of disorders such as disease; palmoplantar pustulosis; pyoderma gangrenosum; Cesar syndrome; atopic dermatitis; systemic sclerosis; and localized scleroderma Widely known. In particular, activity against VEGF expression is useful for treating cancer and VEGF-related disorders. Inhibition of LTB ₄ induced cell migration is useful as an anti-inflammatory agent.

  Thus, the present invention provides a method of treating a disorder associated with the above activity comprising the step of administering at least one compound of formula I to a subject in need thereof in an effective amount. In the methods of the present invention, other therapeutic agents, such as those known to those skilled in the art, may be used with the compounds of the present invention. In the methods of the invention, such other therapeutic agents can be administered before, concurrently with, or after administration of the compounds of the invention.

  Examples of pharmaceutical compositions include all solids (tablets, pills, capsules, granules, powders, suppositories, etc.) or liquids (solutions, suspensions) in the form of compositions suitable for oral, topical, parenteral or rectal administration. Suspension or emulsion). These formulations may contain pure compounds or may be in combination with carriers or other pharmacologically active compounds. These compositions must be sterile when administered parenterally.

  For topical use, it is preferably used in the form of a cream, ointment, jelly, solution or suspension containing the compound of formula I (for purposes of this application, topical administration is a mouthwash And gargles).

  For the treatment of the conditions described above, dosages of about 0.01 mg to about 140 mg per day per kg of body weight or about 0.5 mg to about 7 g per day per patient are useful. For example, inflammation is effectively treated by administering about 0.01 to about 50 mg of compound per kilogram of body weight daily, or about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day. The

  The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, formulations intended for oral administration to humans contain 0.5 mg to 5 g of active material mixed with a suitable and easy-to-use amount of carrier material between about 5 to about 95% of the total composition amount. Single dose dosage forms generally contain from about 1 mg to about 500 mg of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg of active ingredient.

  However, the specific dosage for an individual patient may vary, including age, weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination and the extent of the disease being treated. It will be understood that this depends on various factors.

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

Synthesis of compounds (Example 1)
4- [2- (3,5-Dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid (1)
a) Methyl 3,5-dimethoxy-4-i-propylbenzoate This compound was obtained using the method described in WO 01/42231. ¹ HNMR (CDCl ₃ , ppm): δ1.32 (d, J = 7.2Hz, 6H), 3.66 (hept, J = 7.2Hz, 1H), 3.82 (s, 6H), 3.95 (s, 3H), 7.25 (s, 2H).
b) 3,5-dimethoxy-4-i-propylbenzyl alcohol
To a suspension of LiAlH ₄ (95%) (5.00 g, 125 mmol) in anhydrous ether (100 mL) at 0 ° C. under N ₂ atmosphere, methyl 3,5-dimethoxy-4-i-propylbenzoate (15.7 g, 90.1 mmol) in ether (300 mL) was added. The suspension was stirred at 0 ° C. for 1 hour and then at room temperature for an additional hour. The reaction was stopped by slowly adding saturated aqueous Na ₂ SO ₄ (10 mL) at 0 ° C. The mixture was stirred overnight. The solid was filtered, and the filtrate was evaporated to dryness to obtain the target alcohol (13.8 g, yield 88%) as white crystals. ¹ HNMR (CDCl ₃ , ppm): δ1.34 (d, J = 7.2Hz, 6H), 3.65 (Hept., J = 7.2Hz, 1H), 3.88 (s, 6H), 4.70 (s, 2H), 6.62 (s, 2H).
c) 3,5-Dimethoxy-4-i-propylbenzylaldehyde
Mixture of 3,5-dimethoxy-4-i-propylbenzyl alcohol (13.05 g, 62.1 mmol) and pyridinium chlorochromate (33.92 g, 157 mmol) in CH ₂ Cl ₂ (100 mL) with K ₂ CO ₃ (4.18 g , 30 mmol) for 30 minutes. Ether (300 mL) was added to quench the reaction. The mixture was passed through a short pad of Florosil and the pad was thoroughly washed with ether. The solvent was evaporated to give 3,5-dimethoxy-4-i-propylbenzylaldehyde (11.89 g, 92% yield) as yellowish crystals. ¹ HNMR (CDCl ₃ , ppm): δ1.32 (d, J = 7.2Hz, 6H), 3.68 (hept., J = 7.2Hz, 1H), 3.92 (s, 6H), 7.12 (s, 2H), 9.96 (s, 1H).
d) A suspension of (3,5-dimethoxy-4-i-propylphenyl) ethene methyltriphenylphosphonium bromide (6.89 g, 19.3 mmol) in THF (100 mL) was added to BuLi (7.7 ml, 2.5M in hexane, 19.3 mmol). The resulting red solution was stirred for 10 minutes before 3,5-dimethoxy-4-i-propylbenzylaldehyde (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 × 100 mL). The extract was washed with saturated brine (3 × 30 mL) and dried over sodium sulfate. After evaporation of the ether, flash chromatography with 3% ethyl acetate-hexane was performed to obtain pure (3,5-dimethoxy-4-i-propylphenyl) ethene (2.64 g, 66% yield). Obtained as a colorless solid. ¹ HNMR (CDCl ₃ , ppm): δ1.31 (d, J = 7.1Hz, 6H), 3.61 (qint, J = 7.1Hz, 1H), 3.86 (s, 6H), 5.25 (d, J = 11Hz, 1H), 5.73 (d, J = 17Hz, 1H), 6.64 (s, 2H), 6.70 (dd, J = 11, 17Hz, 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), 4-bromobenzoic acid (0.269 g, 1.30 mmol), dihydrogen di-μ-chlorotetrakis (di-tert-butyl) Phosphinite-κP) diparadate (dihydrogen di-μ-chlorotetrkis (di-tert-butylphosphinito-κP) dipalladate) (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) in DMF (7 ml) was heated to 140 ° C. under an argon atmosphere. After the reaction was complete (5 hours), the reaction mixture was poured into water (100 mL). This 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): δ1.32 (d, J = 7.1Hz, 6H), 3.63 (qint, J = 7.1Hz, 1H), 3.90 (s, 6H), 6.76 (s, 2H), 7.08 (d, J = 17Hz, 1H), 7.27 (d, J = 17Hz, 1H), 7.63 (d, J = 8Hz, 2H), 8.13 (d, J = 8Hz, 2H).

(Example 2)
3- [2- (3,5-Dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid (2)
This compound was synthesized in 77% yield by a method similar to the preparation of 1 from (3,5-dimethoxy-4-i-propylphenyl) ethene and 3-bromobenzoic acid. ¹ HNMR (CDCl ₃ , ppm): δ1.32 (d, J = 7.1Hz, 6H), 3.63 (qint, J = 7.1Hz, 1H), 3.90 (s, 6H), 6.76 (s, 6H), 7.08 (d, J = 17Hz, 1H), 7.25 (d, J = 17Hz, 1H), 7.50 (t, J = 7.7Hz, 1H), 7.79 (d, J = 7.7Hz, 1H), 8.04 (d, J = 7.7Hz, 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 g, 5.9 mmol) was placed under argon vapor for 2 hours. And heated to 200 ° C. 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 × 50 mL). The extract was washed with saturated brine and dried over anhydrous Na ₂ SO ₄ . After evaporation of ether, flash chromatography with ethyl acetate / hexane / acetic acid (40/60/1) was performed to obtain pure acid 6 (0.03 g, yield 11%). ¹ HNMR (DMSO-d ₆ , ppm): δ1.22 (d, J = 7.0Hz), 6.49 (s, 2H), 6.90 (d, J = 18Hz, 1H), 7.19 (d, J = 18Hz, 1H ), 7.67 (d, J = 8Hz, 2H), 7.90 (d, J = 8Hz, 2H), 9.14 (s, 2H).

Example 4
3- [2- (3,5-Dihydroxy-4-i-propylphenyl) ethenyl] benzoic acid (7)
This material was prepared in 86% yield from 3- [2- (3,5-dimethoxy-4-i-propylphenyl) ethenyl] benzoic acid 2 and pyridine hydrochloride by a method similar to Example 3. It was done. ¹ HNMR (DMSO-d ₆ , ppm): δ1.22 (d, J = 7.0Hz, 6H), 6.48 (s, 2H), 7.03 (d, J = 17Hz, 1H), 7.12 (d, J = 17Hz , 1H), 7.46 (t, J = 7.5Hz, 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 to 110-130 ° C. overnight in the presence of Bu ₄ NI (0.05 g). Excess triethyl phosphite was removed at 110 ° C. under reduced pressure. The phosphonate ester (23 g) was obtained quantitatively as a colorless liquid. ¹ HNMR (CDCl ₃ , ppm): δ1.28 (t, J = 7.2Hz, 6H), 3.20 (d, J = 21.9Hz, 2H), 4.10 (dt., J = 7.2Hz, 7.2Hz, 4H) , 7.30 (s, 5H).

b) 1- (3,5-Dimethoxy-4-i-propylphenyl) -2-phenylethene (19)
To a solution of diethyl benzylphosphonate (11.39 g, 54.7 mmol) obtained above in THF (100 mL) was added NaH (60% in mineral oil) (4.68 g, 115 mmol) at 0 ° C. under N ₂ atmosphere. After the addition was complete, the suspension was stirred at 0 ° C. for 1 hour, and 3,5-dimethoxy-4-i-propylbenzylaldehyde (11.39 g, 54.7 mmol) of THF obtained in Example 1 (c) was obtained. (100 mL) solution was added. The reaction was kept 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 2N HCl (75 mL). The mixture was extracted with ether (3 × 200 mL). The extract was dried over anhydrous Na ₂ SO ₄ . The ether was evaporated to give crude 5- (2-phenylethenyl) -2-i-propyl-1,3-dimethoxybenzene (18.07 g). This was used in the next reaction without further purification. A small amount of the crude product was purified by flash chromatography using 10% ethyl acetate-hexane to give the pure product. ¹ HNMR (CDCl ₃ , ppm): δ1.28 (d, J = 7.0Hz, 6H), 3.58 (hept, J = 7.0Hz, 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)
Crude 1- (3,5-dimethoxy-4-i-propylphenyl) -2-phenylethene (18.07 g) in anhydrous CH ₂ Cl ₂ (100 mL) was added to BBr ₃ (-78 ° C. under N ₂ atmosphere at −78 ° C. 5.2 mL, 55 mmol) was added dropwise. The reaction was stirred at −78 ° C. for 1 hour, then the temperature was returned to room temperature and the reaction mixture was stirred at room temperature for 2 days. After adding water to stop the reaction, 20% NaOH was added to adjust pH> 12. The organic layer was removed and the aqueous layer was washed with hexane (2 × 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 syrupy liquid. Recrystallization from chloroform gave pure stilbene product 20 (6.92 g) as white crystals. The remaining liquid was concentrated and the residue was recrystallized once more to give another 2.5 g of 20 (9.42 g combined, 67.7% over 2 steps). ¹ HNMR (CDCl ₃ , ppm): δ1.38 (d, J = 7.3Hz, 6H), 3.46 (hept., J = 7.3Hz, 1H), 4.80 (s, 2H), 6.50 (s, 2H), 6.92 (d, J = 17.2Hz, 1H), 6.97 (d, J = 17.2Hz, 1H), 7.25 (m, 1H), 7.34 (m, 2H), 7.52 (m, 2H).

(Example 7)
3-Acetoxy-5- (2-phenylethenyl) -2-i-propylphenylacetate (10)
5- (2-Phenylethenyl) -2-i-propyl-1,3-benzenediol (1.00 g, 3.93 mmol) and triethylamine (1.5 mL, 10.8 mmol) obtained in Example 11 in dichloromethane (100 mL). mmol) was added dropwise with acetyl chloride at 0 ° C. The reaction was monitored by TLC. After the reaction was complete (˜30 minutes), 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. After evaporation of the solvent, flash chromatography with 5% ethyl acetate-hexane was performed to give 3-acetoxy-5- (2-phenylethenyl) -2-i-propylphenyl acetate (1.32 g, 92%) Was obtained as a white solid. ¹ HNMR (CDCl ₃ , ppm): δ1.26 (d, J = 7.0Hz, 6H), 2.35 (s, 6H), 3.08 (hept., J = 7.0Hz, 1H), 6.98 (d, J = 17.4 Hz, 1H), 7.04 (d, J = 17.4Hz, 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-propylphenylchloroacetate (11)
This material was prepared from 72% of chloroacetic anhydride and 5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol obtained in Example 11 by the same method as in Example 12. Synthesized in yield. ¹ HNMR (CDCl ₃ , ppm): δ1.30 (d, J = 7.0Hz, 6H), 3.08 (hept, J = 7.0Hz, 1H), 4.39 (s, 4H), 6.96 (d, J = 17Hz, 1H), 7.14 (d, J = 17Hz, 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-isopropylbenzyl bromide To 3,5-dimethoxy-4-i-propylbenzyl alcohol (12.57 g, 59.8 mmol) in anhydrous ether (100 mL) at 0 ° C. under nitrogen atmosphere ₃ (3.0 mL, 31.2 mmol) was added dropwise. The reaction was monitored by TLC. After the reaction was complete (˜4 hours), water (180 mL) was added. The organic layer was separated and the aqueous layer was extracted with ether (3 × 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 solvent was evaporated to give pure bromide (14.93 g, 91.4%) as a white solid. ¹ HNMR (CDCl ₃ , ppm): δ1.29 (d, J = 7.1Hz, 6H), 3.64 (hept, J = 7.1Hz, 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-isopropylbenzyl bromide (5.01 g, 18.3 mmol) and triethyl phosphite (4.7 mL, 27.4 mmol) was prepared overnight at 110-130 in the presence of Bu ₄ NI (0.05 g). Heated to ° C. Excess triethyl phosphite was removed under reduced pressure at 110 ° C. to give the phosphonate (5.58 g, 92%). ¹ HNMR (CDCl ₃ , ppm): δ1.27 (d, J = 7.1Hz, 6H), 1.29 (t, J = 7.0Hz, 6H), 3.12 (d, J = 21.5Hz, 2H), 3.4-3.7 (m, 1H), 3.80 (s, 6H), 4.06 (dt, J = 7.1, 7.1Hz, 4H), 6.50 (d, J = 2.6Hz, 2H).

c) 1- (3,5-Dimethoxy-4-i-propylphenyl) -2- (4-methoxyphenyl) ethene (12)
This material was prepared in 63% yield from diethyl (3,5-dimethoxy-4-i-propylbenzyl) phosphonate and 4-anisaldehyde by a method similar to Example 5 (b). ¹ HNMR (CDCl ₃ , ppm): δ1.31 (d, J = 7.1Hz, 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)
This material was obtained in 30% yield from 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (4-methoxyphenyl) ethene and pyridine hydrochloride in the same manner as in Example 3. Was prepared. ¹ HNMR (DMSO-d ₆ , ppm): δ1.22 (d, J = 7.0Hz, 6H), 3.41 (m, 1H), 6.40 (s, 2H), 6.73 (d, J = 6.3Hz, 4H) , 7.33 (s, 1H), 7.41 (s, 1H), 8.98 (s, 2H), 9.51 (s, 1H).

(Example 11)
1- (3,5-Dimethoxy-4-i-propylphenyl) -2- (3,5-dimethoxyphenyl) ethene (14)
This material was prepared in 25% yield from diethyl (3,5-dimethoxy-4-i-propylbenzyl) phosphonate and 3,5-dimethoxybenzaldehyde by a method similar to Example 5 (b). It was.

(Example 12)
5- [2- (3,5-Dihydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol (15)
This material was prepared from 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3,5-dimethoxyphenyl) ethene and BBr _{3 in} a manner similar to Example 11.

(Example 13)
1- (4-Bromo-3,5-dimethoxyphenyl) -2-phenylethene (21)
a) Methyl 4-bromo-3,5-dimethoxybenzoate This material was prepared from 4-bromo-3,5-dihydroxybenzoic acid and Me ₂ SO ₄ by 95% according to the same method as in Example 1 (a). Was synthesized in a yield of 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 This material was obtained from the methyl 4-bromo-3,5-dimethoxybenzoate obtained above in 89% by the same method as in Example 1 (b). Was synthesized in a yield of 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 This material was synthesized from 4-bromo-3,5-dimethoxybenzyl alcohol in a 75% yield by a method similar to 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)
This material was synthesized in 70% yield from 4-bromo-3,5-dimethoxybenzylaldehyde and diethyl benzylphosphonate by a method similar to Example 5 (b). ¹ HNMR (CDCl ₃ , ppm): δ 3.96 (s, 6H), 6.72 (s, 2H), 7.06 (d, J = 17Hz, 1H), 7.11 (d, J = 17Hz, 1H), 7.28 (m, 1H), 7.37 (m, 2H), 7.55 (m, 2H).

(Example 14)
2-Bromo-5- (2-phenylethenyl) -1,3-benzenediol (22)
This material was synthesized in 90% yield from 1- (4-bromo-3,5-dimethoxyphenyl) -2-phenylethene (21) and BBr ₃ by the same method as in Example 6. ¹ HNMR (CDCl ₃ , ppm): δ 5.39 (s, 2H), 6.81 (s, 2H), 7.06 (d, J = 17Hz, 1H), 7.11 (d, J = 17Hz, 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)
To a solution of 1- (4-bromo-3,5-dimethoxyphenyl) -2-phenylethene (0.2185 g, 0.6845 mmol) in anhydrous THF (10 mL) at −78 ° C., BuLi (0.3 mL, 2.5 M, in hexane, 0.7530 mmol) was added. One hour after the addition, benzaldehyde (0.07 mL, 0.69 mmol) was added. The reaction mixture was stirred at −78 ° C. for a further 4 hours and then quenched with water (12 mL). This was extracted with ether (3 × 20 mL). The extracts were combined and dried over anhydrous Na ₂ SO ₄ . After evaporation of the solvent, flash chromatography with 5% ethyl acetate-hexanes gave pure 16 (0.203 g, 86% yield) as a yellow solid. ¹ HNMR (CDCl ₃ , ppm): δ 3.88 (s, 6H), 4.26 (d, J = 5.6Hz, 1H), 6.40 (br, 1H), 6.79 (s, 2H), 7.12 (s, 2H) , 7.2-7.6 (m, 10H).

(Example 16)
2,5-Dimethoxy-4- (2-phenylethenyl) benzaldehyde (17)
This compound was synthesized from 1- (4-bromo-3,5-dimethoxyphenyl) -2-phenylethene, BuLi and N, N-dimethylformamide in a 38% yield by a method similar to Example 15. It was. ¹ HNMR (CDCl ₃ , ppm): δ3.94 (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) at −78 ° C. in t-butyllithium (1.1 mL, 1 M, THF) ) Was added. After the addition was complete, the solution was heated slowly to reflux for 30 minutes and then cooled to -78 ° C. Ethyl iodide (1.2 eq, 0.27 mL) was added to the solution. After the reaction was complete, water (10 mL) was added. The 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 solution was evaporated and flash chromatographed with 20% ether-hexane to give 1,3-dimethoxy-2-ethyl-5- (2-phenylethenyl) benzene in 70% yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.12 (t, J = 7.2Hz, 6H), 2.70 (q, J = 7.2Hz, 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)
This material was synthesized from 1- (3,5-dimethoxy-4-ethylphenyl) -2-phenylethene and BBr _{3 in} the same manner as in Example 6 in 91% yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.22 (t, J = 7.5Hz, 6H), 2.70 (q, J = 7.5Hz, 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)
This material was prepared in a similar manner as Example 15 from 2-bromo-1,3-dimethoxy-5- (2-phenylethenyl) benzene and 1-bromo-n-tetradecane. 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, 1H), 7.36 (m, 2H), 7.52 (m, 2H).

(Example 20)
5- (2-Phenylethenyl) -2-n-tetradecanyl-1,3-benzenediol (26)
This material was synthesized from 1- (3,5-dimethoxy-4-n-tetradecanylphenyl) -2-phenylethene and BBr _{3 in} the same manner as 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, 1H), 7.36 (m, 2H), 7.52 (m, 2H).

(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) at 0 ° C. under N ₂ atmosphere, NaH (60%, in mineral oil) (0.14 g, 3.5 mmol) was added. After the addition was complete, the suspension was stirred at 0 ° C. for 1 h and then a solution of 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 × 20 mL). The extract was dried over anhydrous Na ₂ SO ₄ . After evaporation of the ether, flash chromatography using 5% ethyl acetate-hexane as eluent gave 2- (3,5-dimethoxy-4-i-propylphenyl) -1- (2-fluorophenyl) Ethene (1) was obtained. ¹ HNMR (CDCl ₃ , ppm): δ 1.34 (d, J = 7.1Hz, 6H), 3.60 (qint. J = 7.1Hz, 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)
This material was prepared in a manner similar to Example 21 from diethyl (3,5-dimethoxy-4-i-propylbenzyl) phosphonate and 3-fluorobenzaldehyde.

(Example 23)
1- (3,5-Dimethoxy-4-i-propylphenyl) -2- (4-fluorophenyl) ethene (29)
This material was prepared in a manner similar to Example 21 from diethyl (3,5-dimethoxy-4-i-propylbenzyl) phosphonate and 4-fluorobenzaldehyde.

(Example 24)
2- (3,5-Difluorophenyl) -1- (3,5-dimethoxy-4-i-propylphenyl) ethene (30)
This material was prepared in 27% yield from (3,5-dimethoxy-4-i-propylbenzyl) phosphonate and 3,5-difluorobenzaldehyde by a method similar to Example 21. ¹ HNMR (CDCl ₃ , ppm): δ 1.32 (d, J = 7.0Hz, 6H), 3.66 (qint., J = 7.0Hz, 1H), 3.90 (s, 6H), 6.72 (s, 2H), 6.8 -7.2 (m, 5H).

(Example 25)
1- (2,4-Difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethene (31)
A suspension of (3,5-dimethoxy-4-i-propylphenyl) ethene methyltriphenylphosphonium bromide (6.89 g, 19.3 mmol) in THF (100 mL) was added BuLi (7.7 mL, 2.5M, 19.3 mmol) in hexane was added. The resulting red solution was stirred for 10 minutes, and then a solution of 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 × 100 mL). The extract was washed with saturated brine (3 × 30 mL) and dried over sodium sulfate. After evaporation of the ether, flash chromatography with 3% ethyl acetate-hexane was performed, and pure (3,5-dimethoxy-4-i-propylphenyl) ethene (2.64 g, 66% yield) was colorless. As a solid. ¹ HNMR (CDCl ₃ , ppm): δ 1.31 (d, J = 7.1Hz, 6H), 3.61 (qint, J = 7.1Hz, 1H), 3.86 (s, 6H), 5.25 (d, J = 11Hz, 1H ), 5.73 (d, J = 17Hz, 1H), 6.64 (s, 2H), 6.70 (dd, J = 11, 17Hz, 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), dihydrogen di-μ-chlorotetrakis ( Di-tert-butylphosphinite-κP) diparadate (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) in DMF (10 mL) And heated to 140 ° C. under an argon atmosphere. After the reaction was complete (6 hours), the reaction mixture was poured into water (10 mL). The aqueous phase was acidified with 2N HCl and extracted with ether (2 × 50 mL). The extract was washed with saturated sodium chloride solution and then dried over anhydrous Na ₂ SO ₄ . After evaporating the ether, flash chromatography with 2% ethyl acetate-hexane was performed to give 1- (2,4-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethene. (31) was obtained quantitatively as yellowish crystals. ¹ HNMR (CDCl ₃ , ppm): δ 1.32 (d, J = 7.1Hz, 6H), 3.63 (qint, J = 7.1Hz, 1H), 3.90 (s, 6H), 6.76 (s, 2H), 7.08 ( d, J = 17Hz, 1H), 7.27 (d, J = 17Hz, 1H), 7.63 (d, J = 8Hz, 2H), 8.13 (d, J = 8Hz, 2H).

(Example 26)
1- (2,6-Difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethene (32)
This compound was synthesized quantitatively from (3,5-dimethoxy-4-i-propylphenyl) ethene and 1-bromo-2,6-difluorobenzene by a method similar to the preparation of 31. ¹ HNMR (CDCl ₃ , ppm): δ1.32 (d, J = 7.1Hz, 6H), 3.62 (qint, J = 7.1Hz, 1H), 3.90 (s, 6H), 6.73 (s, 2H), 6.8 -7.2 (m, 4H), 7.41 (d, J = 16.6Hz, 1H).

(Example 27)
1- (3,5-Dimethoxy-4-i-propylphenyl) -2- (2,4,6-trifluorophenyl) ethene (33)
This compound was synthesized in 58% yield from (3,5-dimethoxy-4-i-propylphenyl) ethene and 1-bromo-2,4,6-trifluorobenzene by a method similar to the preparation of 31 It was done. ¹ HNMR (CDCl ₃ , ppm): δ1.32 (d, J = 7.0Hz, 6H), 3.62 (qint, J = 7.1Hz, 1H), 3.89 (s, 6H), 6.73 (s, 2H), 6.79 -7.55 (m, 4H).

(Example 28)
1- (3,5-Dimethoxy-4-i-propylphenyl) -2- (2,3,4,5,6-pentafluorophenyl) ethene (34)
This compound was synthesized from (3,5-dimethoxy-4-i-propylphenyl) ethene and 1-bromo-2,3,4,5,6-trifluorobenzene by a method similar to the preparation of 31. .

(Example 29)
5- [2- (2-Fluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (37)
A mixture of 2- (3,5-dimethoxy-4-i-propylphenyl) -1- (2-fluorophenyl) ethene (27) (0.308 g, 1.03 mmol) and pyridine hydrochloride (0.72 g, 6.2 mmol) And heated to 200 ° C. under argon vapor 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 × 10 mL). The extract was dried over anhydrous Na ₂ SO ₄ . The ether was evaporated and flash chromatographed with 15% ethyl acetate-hexane to give pure 5- [2- (2-fluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (37) (0.269 g, 95% yield) was obtained as a whitish solid. ¹ HNMR (CDCl ₃ , ppm): δ 1.41 (d, J = 7.2Hz, 6H), 3.51 (qint., J = 7.2Hz, 1H), 5.01 (b, 2H), 6.56 (s, 2H), 6.98 (d, J = 17.6Hz, 1H), 7.0-7.3 (m, 4H), 7.60 (ddd, J = 7.5, 7.5, 2.2Hz, 1H).

(Example 30)
5- [2- (3-Fluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol (38)
This material was prepared from 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3-fluorophenyl) ethene (28) and pyridine hydrochloride by a method similar to Example 34. . ¹ HNMR (CDCl ₃ , ppm): δ 1.41 (d, J = 7.2Hz, 6H), 3.49 (qint., J = 7.2Hz, 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)
This material was prepared from 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (4-fluorophenyl) ethene (29) and pyridine hydrochloride by a method similar to Example 34. (Yield 38% in two steps). ¹ HNMR (CDCl ₃ , ppm): δ 1.41 (d, J = 7.2Hz, 6H), 3.48 (qint., J = 7.2Hz, 1H), 6.52 (s, 2H), 6.81 (d, J = 17Hz, 1H), 7.00 (d, J = 17Hz, 1H), 7.0-7.2 (m, 2H), 7.4-7.6 (m, 2H); ¹ HNMR (DMSO-d6, ppm): δ 1.22 (d, J = 7.1 Hz, 6H), 3.35 (qint., J = 7.1Hz, 1H), 6.45 (s, 2H), 6.81 (d, J = 16.7Hz, 1H), 6.99 (d, J = 16.7Hz, 1H), 7.17 (dd, J = 8.8, 8.8Hz, 2H), 7.61 (dd, J = 8.8Hz, 5.6Hz, 2H), 9.05 (s, 2H).

(Example 32)
5- [2- (3,5-Difluorophenyl) ethenyl] -2-i-propylphenyl-1,3-diol (40)
This material was prepared from 70% of 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (3,5-difluorophenyl) ethene and pyridine hydrochloride by a method similar to Example 34. Prepared in yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.40 (d, J = 7.1Hz, 6H), 3.56 (qint., J = 7.2Hz, 1H), 4.90 (s, 2H), 6.52 (s, 2H), 6.2 -7.1 (m, 5H).

(Example 33)
5- [2- (2,4-Difluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (41)
This material is 44% of 1- (2,4-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethene and pyridine hydrochloride by a method similar to Example 34. Prepared in yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.41 (d, J = 7.1Hz, 6H), 3.49 (qint., J = 7.1Hz, 1H), 4.78 (br, 2H), 6.54 (s, 2H), 6.69 -7.02 (m, 3H), 7.13 (d, J = 16Hz, 1H), 7.41-7.75 (m, 1H).

(Example 34)
5- [2- (2,6-Difluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (42)
This material was 29% of 1- (2,6-difluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethene and pyridine hydrochloride by a method similar to Example 34. Prepared in yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.42 (d, J = 7.1Hz, 6H), 3.50 (qint, J = 7.1Hz, 1H), 4.77 (br, 2H), 6.57 (s, 2H), 6.8- 7.4 (m, 5H).

(Example 35)
2-i-propyl-5- [2- (2,4,6-trifluorophenyl) ethenyl] -1,3-benzenediol (43)
This material was prepared from 1- (3,5-dimethoxy-4-i-propylphenyl) -2- (2,4,6-trifluorophenyl) ethene and pyridine hydrochloride by a method similar to Example 29. % Yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.42 (d, J = 7.1Hz, 6H), 3.50 (qint, J = 7.1Hz, 1H), 4.77 (br, 2H), 6.55 (s, 2H), 6.59- 7.24 (m, 4H).

(Example 36)
5- [2- (2,3,4,5,6-pentafluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol (44)
This material was similar to Example 34 from 1- (2,3,4,5,6-pentafluorophenyl) -2- (3,5-dimethoxy-4-i-propylphenyl) ethene and pyridine hydrochloride. Was prepared in 21% yield. ¹ HNMR (CDCl ₃ , ppm): δ 1.40 (d, J = 7.2Hz, 6H), 3.53 (d, J = 7.2Hz, 6H), 4.91 (s, 2H), 6.55 (s, 2H), 6.86 ( d, J = 17Hz, 1H), 7.28 (d, J = 17Hz, 1H).

  By standard pharmacological methods described in detail in the examples below, the compounds of the invention inhibit T-cell, keratinocyte proliferation, leukotriene B4 induced cell migration, and in vitro. It is shown to inhibit IFN-γ secretion and VEGF expression, and inhibit TNF-α and edema in vivo.

(Example 37)
Biological Activity of Novel Compounds The following assays for biological activity are established and known to those skilled in the art. Here is a brief description to help understanding.

(a) Proliferation of human peripheral blood mononuclear cells (PBMC) stimulated by phytohemagglutinin (PHA) and effects on IFN-γ production: PBMC were cultured with PHA using standard cell culture techniques, Incubated with titrated concentrations of compound or solvent, or in medium alone. MTT assay was performed after 48 hours of culture. Supernatants were collected after 48 hours of culture and assayed for IFN-γ levels by ELISA.

Results: The 5- [2- (4-hydroxyphenyl) ethenyl] -2-i-propyl-1,3-benzenediol (13) of the present invention had an IC ₅₀ of 2.97 for human PBMC proliferation. In contrast, resveratrol had an IC ₅₀ greater than ₅₀ . Compound 13 is 20 times more potent in inhibiting PBMC proliferation (Table 1). Similarly, compound 13 is more than 15 times more potent than resveratrol at inhibiting IFN-γ production (Table 2). Similarly, the three fluorinated compounds, 37, 38 and 39, had an IC ₅₀ of less than 10 μM, while resveratrol had an IC ₅₀ of greater than 50 μM, the highest concentration tested. The fluorinated compounds had superior activity, with a potency greater than 5 times that of resveratrol, on inhibition of PBMC proliferation (Table 1). Similarly, resveratrol has an IC ₅₀ value that is more than 9 times higher than that of the three fluorinated compounds, and that the fluorinated compounds are more than 9 times more potent than resveratrol against the inhibition of IFN-γ production by human PBMC. (Table 2).

(b) Effect on proliferation of human keratinocytes Human keratinocytes were cultured in the presence of IFN-γ and titrated concentrations of drug or carrier. MTT assay was performed after 48 hours of culture.

Results: Compound 13 had an IC ₅₀ of 4.3 μM, while resveratrol had an IC ₅₀ greater than ₅₀ . This indicates that compound 13 is more than 10 times more potent than resveratrol (Table 3).

(c) Effect on human leukocyte (WBC) migration induced by leukotriene B4: WBC collected from donors were mixed with an equal volume of 3% dextran (in 0.15 M NaCl). Red blood cells were sedimented (room temperature, 45 minutes) and removed. All remaining red blood cells in the plasma were removed by adding 150 mM Tris-NH ₄ Cl. The resulting white blood plasma
Washed twice in Hank's solution containing 20 mM HEPES. The WBC was then transferred to RPMI-1640 medium and the density was adjusted to 5 × 10 ⁷ cells / ml. WBC migration was measured using an agarose plate assay system (Nelson et al., 1978). Briefly, a 0.8% agarose solution was prepared using complete RPMI-1640 cell culture. Approximately 3.5 ml of this agarose solution was transferred to a glass slide before it solidified. After agarose solidified, wells were made on a slide glass with a 3 × 6 array (φ2 mm, distance between wells 3 mm). LTB4 was dissolved in absolute ethanol at 10 ⁴ ng / ml and further diluted to 10 ng / ml with RPMI-1640 medium for testing. Compound 39 was dissolved in DMSO, diluted to 10 ³ μg / ml with RPMI-1640 and tested at concentrations of 100, 10, 1, 0.1 and 0.01 μg / ml. 10 μl of cell suspension containing different concentrations of compound 39 was added to each well in the middle row of the three rows of wells. Controls were made by adding the same volume of LTB ₄ to RPMI-1640 medium or medium alone to the other rows of wells. After 5 hours incubation (5% CO ₂ , 37 ° C.), test slides were fixed with 100% methanol (30 minutes) and dried at 4 ° C. (overnight). Next, the slide glass was examined with a microscope. The migration index was defined as the average distance a cell migrated towards a well with LTB ₄ divided by that of spontaneous migration. The percentage of migration was compared between the treated and no drug controls. A dose-effect relationship was determined by plotting the percentage of chemotaxis against the concentration of IC ₅₀ values.

Results: Compound 39 inhibited migration of WBC to LTB _{4 in} a dose dependent manner (Table 4).

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

(d) Experiment on effect on vascular endothelial growth factor (VEGF) protein expression: Compound 39 was dissolved in DMSO and diluted to 10 ³ μg / ml with keratinocyte-serum free medium (KC-SFM). Further dilutions were tested at concentrations of 10, 1, 0.1 and 0.01 μg / ml. Primary cultures of keratinocytes were purchased and maintained at a cell density of 10 ⁶ / ml with KC-SFM. In the test, cells were cultured in 24-well plates and first incubated for 4 hours at 37 ° C. in 5% CO ₂ before rhTGF-α (final concentration 100 ng / ml) and different concentrations of test compound (0.01-10 μg / ml). ml). As a negative control, media without test compound was also tested. After further incubation for 24 hours, culture supernatants from each well were collected separately and centrifuged at 2000 rpm for 5 minutes to measure VEGF concentration. Using ELISA kits, the VEGF concentration in the supernatant of each well was calculated based on the measurements obtained according to the manufacturer's instructions.

Results: Compound 39 showed a dose-dependent effect on VEGF concentration in the cell supernatant of keratinocytes induced by rhTGF-α after treatment for 24 hours. This effect increased substantially, with 100% decrease in protein concentration when the concentration of compound 39 was increased to 40M (Table 5).

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

(e) In Vivo Efficacy Experiment in Endotoxemia Mouse Model: The test compound was dissolved in 50% PEG-400 aqueous solution and formulated. Female Balb / c mice (~ 20 g) are first injected intraperitoneally (IP) with 25 mg / kg of each test compound, then 30 mg later with 40 mg / kg lipopolysaccharide (LPS) (IP). To attack. Simultaneously with LPS challenge, one drug injection with 12.5 mg / kg test compound was given, followed by two more injections at 30 minute intervals. The positive control dexamethasone was administered in the same manner with 3 additional injections starting at 0.4 mg / kg followed by 0.2 mg / kg. Mice were killed 150 minutes after LPS challenge and blood was collected by cardiac puncture. Serum TNF-α levels were measured by ELISA. Six mice were used in each test group. A group of mice injected with vehicle alone was used as a negative control.

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

Conclusion: Fluorinated compounds, compounds 37 and 39, significantly reduced the level of TNF-α that modulates a wide range of activities in mice. As a result, it reduces the inflammatory response in animals.

(f) Efficacy experiments against TPA-induced edema: three representative compounds, 5- (2-phenylethenyl) -2-, a previously reported related stilbene derivative (WO 0142231) 10-12 female mice per week using i-propyl-1,3-benzenediol and Compound 39, a novel compound of the present invention, with 0.01% calcitriol (commercial standard) as a positive control Assayed for (Balb / c) edema. Phorbol-12-myristate-13-acetate (TPA) was used as an edema inducer. All TPA and test compounds were dissolved in 100% ethanol and 20 μl was applied to the right ear of mice. Six mice were used per group. The TPA concentration used was 0.01% (w / v). Ear thickness was measured 6 hours after TPA treatment to determine if edema was reduced. In each experiment, similarly treated TPA groups of mice were either 5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol, calcitriol, compound 39, or ethanol alone. It was processed by. The level of inhibition was obtained by measuring the ear thickness, and the difference in thickness between treated and ethanol treated ears was expressed as a percentage.

Results: Fluorinated compounds significantly reduce edema. By replacing one of the H atoms of the previously reported stilbene, 5- (2-phenylethenyl) -2-i-propyl-1,3-benzenediol, with F, the novel compound 39 of the present invention is obtained. Inhibition of edema increases from 8% to 85%. In contrast, the inhibition of calcitriol is 31%, demonstrating a surprisingly high level of activity of the novel compound 39 of the present invention.

Claims (29)

Formula I:

[Where:
R ¹ is selected from the group consisting of unsubstituted or substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl groups, halo, or COR ⁹ ;
R ² and R ³ are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or acyl;
R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are not H at the same time, but H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl group, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , n = 0-2, OR ¹² , independently selected from the group consisting of cyclic or heterocyclic groups; provided that R ^{When 1} is an unsaturated group containing 1-3 isoprene units, R ⁶ is not a hydroxy or alkoxy group;
R ⁹ is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl, or NR ¹⁰ R ¹¹ , or OR ¹⁰ ;
R ¹⁰ and R ¹¹ are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl;
R ¹² is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or acyl;
Here, the configuration of the double bond of the compound of formula I is E or Z. ]
Or a salt thereof. R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl group, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O ) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , n = 0-2, OR ¹² , independently selected from the group consisting of cyclic or heterocyclic groups (provided that R ⁴ , R ⁵ , The compound according to claim 1, wherein one or more of R ⁶ , R ⁷ and R ⁸ is F). 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 (where R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^2. The compound of claim 1, wherein one or more of ⁸ is COR ⁹ . R ² and R ^3, H, unsubstituted or substituted alkyl, or is independently selected from the group consisting of acyl, The compound of claim 3 wherein. R ² and R ^3, H, methyl, or is independently selected from the group consisting of acetyl 5. The compound of claim 4, wherein. The R ^{1 according} to claim 2, wherein R ¹ is selected from 1 to 14 carbon unsubstituted or substituted alkyl; R ² and R ³ are each independently selected from the group consisting of H, unsubstituted or substituted alkyl or acyl. Compound. R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of H and F, provided that one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ The above is F). 7. A compound according to claim 6, wherein R < ¹ > is isopropyl; R < ² > and R < ³ > are each independently selected from the group consisting of H, methyl or acetyl. Compound is
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-phenylethene;
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;
The compound of claim 1 selected from the group consisting of 5- [2- (2,3,4,5,6-pentafluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol. Formula I:

[Where:
R ¹ is selected from the group consisting of unsubstituted or substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl groups, halo, or COR ⁹ ;
R ² and R ³ are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or acyl;
R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are not H at the same time, but H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl group, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , n = 0-2, OR ¹² , independently selected from the group consisting of cyclic or heterocyclic groups; provided that R ^{When 1} is an unsaturated group containing 1-3 isoprene units, R ⁶ is not a hydroxy or alkoxy group;
R ⁹ is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl, or NR ¹⁰ R ¹¹ , or OR ¹⁰ ;
R ¹⁰ and R ¹¹ are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl;
R ¹² is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or acyl;
Here, the configuration of the double bond of the compound of formula I is E or Z. ]
Or a salt thereof, and a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier. R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl group, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O ) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , n = 0-2, OR ¹² , independently selected from the group consisting of cyclic or heterocyclic groups (provided that R ⁴ , R ⁵ , R ^6, one or more of R ⁷ and R ⁸ are F) the composition 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 (where R ⁴ , R ⁵ , R ⁶ , R ⁷ and R 11. The composition of claim 10, wherein one or more of ⁸ is COR ⁹ . R ² and R ^3, H, unsubstituted or substituted alkyl, or is independently selected from the group consisting of acyl composition of claim 12. R ² and R ^3, H, methyl, or is independently selected from the group consisting of acetyl, The composition of claim 13. 12. R ¹ is selected from unsubstituted or substituted alkyl of 1 to 14 carbons; R ² and R ³ are each independently selected from the group consisting of H, unsubstituted or substituted alkyl or acyl. Composition. R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of H and F, provided that one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ 16. The composition according to claim 15, wherein the above is F). R ¹ is isopropyl; R ² and R ³ are each, H, are selected independently from the group consisting of methyl or acetyl, composition according to claim 15. Compound is
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-phenylethene;
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;
11. A composition according to claim 10, selected from the group consisting of 5- [2- (2,3,4,5,6-pentafluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol. . Formula I:

[Where:
R ¹ is selected from the group consisting of unsubstituted or substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl or aralkyl groups, halo, or COR ⁹ ;
R ² and R ³ are independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or acyl;
R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are not H at the same time, but H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl group, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , n = 0-2, OR ¹² , independently selected from the group consisting of cyclic or heterocyclic groups; provided that R ^{When 1} is an unsaturated group containing 1-3 isoprene units, R ⁶ is not a hydroxy or alkoxy group;
R ⁹ is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl, or NR ¹⁰ R ¹¹ , or OR ¹⁰ ;
R ¹⁰ and R ¹¹ are selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl;
R ¹² is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or acyl;
Here, the configuration of the double bond of the compound of formula I is E or Z. ]
The use of a compound of claim 1 in the manufacture of a medicament for treating disorders including immune, inflammation or autoimmune diseases. R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl group, halo, nitro, CN, COR ⁹ , NR ¹⁰ R ¹¹ , S (O ) ₂ NR ¹⁰ R ¹¹ , S (O) _n R ¹⁰ , n = 0-2, OR ¹² , independently selected from the group consisting of cyclic or heterocyclic groups (provided that R ⁴ , R ⁵ , R ^6, one or more of R ⁷ and R ⁸ are F) the use according to claim 19, wherein. 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 (where R ⁴ , R ⁵ , R ⁶ , R ⁷ and R 20. Use according to claim 19, wherein one or more of ⁸ is COR ⁹ . The use according to claim 21, wherein R ² and R ³ are independently selected from the group consisting of H, unsubstituted or substituted alkyl, or acyl. R ² and R ^3, H, are selected independently from the group consisting of methyl or acetyl, The use according to claim 22, wherein. R ¹ is selected from unsubstituted or substituted alkyl of from 1 to 14 carbon; R ² and R ³ are each, H, unsubstituted or independently from the group consisting of substituted alkyl or acyl selected, according to claim 20, wherein use. R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from the group consisting of H and F, provided that one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ 25. Use according to claim 24, wherein the above is F). R ¹ is isopropyl; R ² and R ³ are each, H, are selected independently from the group consisting of methyl or acetyl, use according to claim 24, wherein. Compound is
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-phenylethene;
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;
20. Use according to claim 19, selected from the group consisting of 5- [2- (2,3,4,5,6-pentafluorophenyl) ethenyl] -2-i-propyl-1,3-benzenediol.   A method of treating a disorder comprising an immune, inflammatory or autoimmune disease in a mammal, comprising administering to the mammal affected by said disorder an effective amount of a compound of formula I as defined in claim 1 or a salt thereof. A method comprising:   A method of treating a disorder comprising an immune, inflammation or autoimmune disease in a mammal, comprising administering an effective amount of a compound or salt thereof according to claim 2 to a mammal affected by said disorder. .