JP2008088183A - Methods for inhibiting vascular cell adhesive molecule-1 and method for treating chronic inflammatory disease using 2,6-dialkyl-4-silylphenol - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a therapeutic drug which can be administrated for inhibiting or treating VCAM-1 mediated action under a condition of such as chronic inflammatory diseases, asthma, rheumatoid arthritis and autoimmune diabetes. <P>SOLUTION: An effective amount of a compound shown by formula (1) wherein R<SB>1</SB>, R<SB>2</SB>, R<SB>3</SB>and R<SB>4</SB>each independently represents a 1-6C alkyl group; Z represents a thio, oxy or methylene group; A represents a 1-4C alkylene group; R<SB>5</SB>represents a 1-6C alkyl or -(CH<SB>2</SB>)<SB>n</SB>-(Ar) group, wherein n represents 0 or an integer of 1, 2 or 3, and Ar represents a phenyl or naphthyl group optionally substituted with 1-3 substituent(s) selected from a group consisting of hydroxy, methoxy, ethoxy, chlorine, fluorine or 1-6C alkyl group(s), is administrated to a patient. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

Vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) are, for example, interleukin-1 (IL-1), interleukin-4 (IL-4) and tumor necrosis factor- It is an adhesion molecule of the immunoglobulin superfamily that is upregulated in vascular endothelium and smooth muscle cells by cytokines such as α (TNF-α). By interacting with the appropriate integrin counter receptor, VCAM-1 and ICAM-1 mediate leukocyte adhesion and transendothelial migration in the inflammatory response. Inhibitors of VCAM-1 and / or ICAM-1 are used for the treatment of many types of chronic inflammatory diseases including asthma, rheumatoid arthritis and autoimmune diabetes. For example, it is known that VCAM-1 and ICAM-1 expression is increased in asthma. Pilewski JM et al . , Am. J. Respir. Cell. Mol. Biol. 12, 1-3 (1995); Ohkawara Y. et al . , Am. J. Respir. Cell. Mol. Biol. 12, 4-12 (1995) . Furthermore, blocking integrin receptors (VLA-4 and LFA-1 respectively) against VCAM-1 and ICAM-1 suppress both early and late responses in an ovalbumin-sensitized rat model of allergic airway responses . Rabb HA et al . , Am. J. Respir. Care Med. 149, 1186-1191 (1994).

Furthermore, VCAM-1 is also implicated as a mediator in other chronic inflammatory diseases such as rheumatoid arthritis and autoimmune diabetes. For example, increased expression of endothelial adhesion molecules including VCAM-1 is seen in the rheumatoid synovial microvasculature. Koch, AE et al . , Lab. Invest. 64, 313-322 (1991); Morales-Ducret, J. et al . , Immunol. 149, 1421-1431 (1992). Neutralizing antibodies directed against VCAM-1 or its counter-receptor VLA-4 can delay the onset of diabetes in a mouse model that spontaneously develops disease (NOD mice). Yang, XD et al . , Proc. Natl. Acad. Sci. USA 90, 10494-10498 (1993); Burkly, LC et al., Diabetes 43, 523-534 (1994); Baron, JL et al . , J. Clin. Invest. 93 1700-1708 (1994). Monoclonal antibodies against VCAM-1 can also have advantageous effects in animal models of allograft rejection, and inhibitors of VCAM-1 expression can be used to prevent graft rejection. Suggests. Orocz, CG et al . , Immunol. Lett. 32, 7-12 (1992).

VCAM-1 is expressed by cells as a membrane-bound form and as a soluble form. The soluble form of VCAM-1 has been shown to induce vascular endothelial cell chemotaxis in vitro and stimulate an angiogenic response in the rat cornea. Koch, AE et al., Nature 376, 517-519 (1995). Inhibitors of soluble VCAM-1 expression have promising therapeutic value in the treatment of diseases with potent angiogenic components including tumor growth and metastasis. Folkman, J. and Shing, Y., J. Biol. Chem. 10931-10934 (1992).

Promoters for both VCAM-1 and ICAM-1 have been cloned and characterized. For example, both promoters contain complex DNA sequence elements capable of binding the transcription factor NF-kB. Iademarco, MF et al . , J. Biol. Chem. 267, 16323-16329 (1992); Voraberger, G. et al . , J. Immunol. 147, 2777-2786 (1991). The NF-kB family of transcription factors is central in the regulation of several genes that are up-regulated within the site of inflammation. Activation of NF-kB as a transcription factor involves dissociation from the inhibitory subunit IkB in the cytoplasm. The NF-kB subunit translocates to the nucleus, binds to specific DNA sequence elements and activates transcription of several genes including VCAM-1 and ICAM-1. Collins T. et al. , Lab. Invest. 68, 499-508 (1993).

Regulation of VCAM-1 gene expression has been postulated to be associated with oxidative stress by specific reduction-oxidation (redox) sensitive transcription or post-transcriptional regulators. Antioxidants pyrrolidine dithiocarbamate and N-acetylcysteine inhibit cytokine-induced expression of VCAM-1 (not ICAM-1) in vascular endothelial cells. Mauri N. et al . , J. Clin. Invest. 92, 1866-1874 (1993). This indicates that inhibition of VCAM-1 by antioxidants is related to some additional factors not involved in the regulation of ICAM-1 expression.

  2,6-Dialkyl-4-silyl-phenol is disclosed as an anti-atherosclerotic agent in US Pat. No. 5,155,250 issued Oct. 13, 1992 by Parker et al. Furthermore, 2,6-dialkyl-4-silyl-phenol is disclosed as a serum cholesterol lowering agent in PCT International Publication No. WO 95/15760 published on June 15, 1995.

  It would be useful to inhibit VCAM-1 release and treat VCAM-1 mediated effects. It is also useful to suppress or treat VCAM-1 inflammation without the concomitant side effects known to accompany the use of anti-inflammatory steroids and non-steroidal anti-inflammatory agents.

〔式中、
R₁、R₂、R₃およびR₄は、それぞれ独立して、C₁〜C₆アルキル基であり；
Ｚは、チオ、オキシまたはメチレン基であり；
Ａは、C₁〜C₄アルキレン基であり；
R₅は、C₁〜C₆アルキルまたは−(CH₂)_n−(Ar）（式中、ｎは整数０、１、２または３であり；そしてArは、置換されていないかまたはヒドロキシ、メトキシ、エトキシ、塩素、弗素またはC₁〜C₆アルキルからなる群から選択された１〜３個の置換分によって置換されているフェニルまたはナフチルである）である〕に相当する化合物は、VCAM−１のサイトカイン−誘発発現を阻害するために使用することができるということが見出された。このような化合物は、VCAM−１を阻害するために；VCAM−１仲介作用を阻害または処置するために；およびVCAM−１仲介炎症を阻害または処置するために患者に投与することができる。化合物は、慢性炎症、喘息、リウマチ様関節炎および自己免疫糖尿病のような状態におけるVCAM−１仲介作用を阻害または処置するために投与することができる。 formula

[Where,
R ₁ , R ₂ , R ₃ and R ₄ are each independently a C ₁ -C ₆ alkyl group;
Z is a thio, oxy or methylene group;
A is C ₁ -C ₄ alkylene group;
R ₅ is C ₁ -C ₆ alkyl or — (CH ₂ ) _n — (Ar), where n is an integer 0, 1, 2, or 3; and Ar is unsubstituted or hydroxy, A compound corresponding to VCAM-, which is phenyl or naphthyl substituted by 1 to 3 substituents selected from the group consisting of methoxy, ethoxy, chlorine, fluorine or C ₁ -C ₆ alkyl It has been found that it can be used to inhibit one cytokine-induced expression. Such compounds can be administered to patients to inhibit VCAM-1; to inhibit or treat VCAM-1-mediated effects; and to inhibit or treat VCAM-1-mediated inflammation. The compounds can be administered to inhibit or treat VCAM-1 mediated effects in conditions such as chronic inflammation, asthma, rheumatoid arthritis and autoimmune diabetes.

How to solve the problem

The term “C ₁ -C ₆ alkyl” as used herein means a saturated hydrocarbyl group containing 1 to 6 carbon atoms in a linear, branched or cyclic arrangement. . The scope of this term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclohexyl and the like.

Similarly, the term “C ₁ -C ₄ alkylene” refers to a saturated hydrocarbyldiyl group in a linear or branched arrangement containing from 1 to 4 carbon atoms. This term includes methylene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl, 1 , 4-butane-diyl and the like.

In the case where R ₅ is a — (CH ₂ ) _n — (Ar) group, the “— (CH ₂ ) _n —” moiety represents a saturated hydrocarbyldiyl group in a linear configuration. “N” is defined as an integer 0, 1, 2, or 3. That is, the moiety “— (CH ₂ ) _n —” represents a single bond, methylene, 1,2-ethanediyl or 1,3-propanediyl. The “— (Ar)” moiety refers to an aryl group defined as a substituted or unsubstituted phenyl or naphthyl group. When the-(Ar) moiety is a substituted aryl, the phenyl or naphthyl can have 1 to 3 substituents at any position occupied by a hydrogen atom. Substituents are hydroxy, methoxy, ethoxy, chlorine, is selected from the group consisting of fluorine and C ₁ -C ₆ alkyl group. In particular, the scope of the term “— (CH ₂ ) _n — (Ar)” includes phenyl; naphthyl; phenylmethyl; phenylethyl: 3,4,5-trihydroxyphenyl; 3,4,5-trimethoxyphenyl; 3,4,5-triethoxyphenyl; 4-chlorophenyl; 4-methylphenyl; 3,5-di-tert-butyl-4-hydroxyphenyl; 4-fluorophenyl; 4-chloro-1-naphthyl; -1-naphthylmethyl; 2-naphthylmethyl; 4-chlorophenylmethyl; 4-tert-butylphenyl, 4-tert-butylphenylmethyl, and the like.

  Compounds of formula (1) can be prepared utilizing procedures and techniques known and recognized by those skilled in the art. A general synthetic scheme for preparing compounds of formula (1) where Z is sulfur or oxygen is as described in Scheme A. In Scheme A, all substituents are as described above unless otherwise stated.

  In general, the phenol of structure 1a is prepared in a suitable aprotic solvent such as acetonitrile, dimethylformamide or dimethylacetamide, or in an aqueous solvent such as water / 2-butanone, suitable 2,6-dialkyl-4 of structure 2. A mercaptophenol or 2,6-dialkylhydroquinone (or a suitably protected derivative) with a non-nucleophilic base such as sodium hydride, potassium carbonate or cesium carbonate and a suitable haloalkylenesilane of structure 3 such as a suitable chloro It can be produced by reacting with an alkylene silane.

The starting materials used in the general synthetic procedure described in Scheme A are readily obtained by those skilled in the art. For example, certain phenol starting materials for various compounds of formula (1) wherein Z is sulfur, such as 2,6-di-tert-butyl-4-mercaptophenol, are described in US Pat. No. 3,576,883, US Pat. No. 3,952,064. No. 3,479,407 and Japanese Patent Application 73-28425. Also, silyl starting materials for various compounds of formula (1) such as (trimethylsilyl) -methyl iodide, (trimethylsilyl) methyl bromide, (trimethylsilyl) methyl chloride, (1-chloropropyl) trimethylsilane are described in Synthesis 4,318. -319 (1988) and J. Am. Chem. Soc. 105, 5665-5675 (1983). Other methods for producing suitable silanes include the Grignard reaction. For example, 4-bromoanisole is reacted with magnesium metal to form a Grignard reagent and this reagent is reacted with chlorodimethylchloromethylsilane to give chloromethyldimethyl-4-methoxyphenylsilane.

Alternatively, anisole can be lithiated by reaction with n-butyllithium and the lithium compound formed can be reacted with chlorodimethylchloromethylsilane to give chloromethyldimethyl-2-methoxyphenylsilane.

  In the case where the 1-phenol function of the compound of structure 2 is reacted with the compound of structure 3 under reaction conditions, the 1-phenol function of the compound of structure 2 is a standard phenol well known and recognized in the art. Can be blocked with a blocking agent. The selection and use of specific blocking groups is well known to those skilled in the art. In general, a blocking group must be selected that sufficiently protects the phenol in question during the next synthetic step and can be easily removed under conditions that do not cause degradation of the desired product.

  Examples of suitable phenol protecting groups are ethers such as methoxymethyl, 2-methoxyethoxymethyl, tetrahydro-pyranyl, t-butyl and benzyl, silyl ethers such as trimethylsilyl and t-butyldimethylsilyl, esters such as acetate and benzoate, Carbonates such as methyl carbonate and benzyl carbonate, and sulfonates such as methane sulfonate and toluene sulfonate.

In the case where R ₁ and R ₂ are each t-butyl, the reaction of Scheme A can be advantageously carried out without blocking the 1-phenol function.

  The following examples show typical syntheses as described in Scheme A. It should be understood that these examples are illustrative only and do not limit the scope of the invention in any way. The following terms have the meanings indicated below. “G” means gram, “mmol” means millimolar, “ml” means milliliter, “bp” means boiling point, “° C.” means degrees Celsius, “mmHg” Means millimeter of mercury, “mp” means melting point, “mg” means milligram, “μM” means micromolar, “μg” means microgram.

2,6−ジ−ｔ−ブチル−４−メルカプトフェノール(2.4ｇ、10ミリモル)、炭酸カリウム(1.4ｇ、10ミリモル）、クロロメチルジメチルフェニルシラン(1.9ｇ、10ミリモル）およびジメチルホルムアミド（50ml）を、混合しそしてアルゴン雰囲気下で室温で一夜撹拌した。混合物を、氷水でうすめそしてエチルエーテルで抽出した。エーテル層を水、それからブラインで洗浄し、フルオロシル−Na₂SO₄を通して濾過しそして蒸発して、オレンジ色の油（3.5ｇ）を得た。生成物を、はじめに蒸留（0.1mmHgにおいて沸点160〜170℃）し、それからシリカゲルクロマトグラフィー処理（CCl₄：CHCl₃／１：１）することによって精製して、明るい黄色の油として標記化合物を得た。この油は、徐々に結晶化して、白色のワックス状の固体(2.3ｇ、59％）を得た。
分析値：C₂₃H₃₄OSSiに対する計算値：C 71.44; H 8.86; S 8.29。実測値：C 71.14; H 8.86; S 7.98。 Example 1
2,6-Di-tert-butyl-4-[(dimethylphenylsilyl) methylthio] phenol (MDL 29,353)

2,6-di-tert-butyl-4-mercaptophenol (2.4 g, 10 mmol), potassium carbonate (1.4 g, 10 mmol), chloromethyldimethylphenylsilane (1.9 g, 10 mmol) and dimethylformamide (50 ml) Were mixed and stirred overnight at room temperature under an argon atmosphere. The mixture was diluted with ice water and extracted with ethyl ether. The ether layer was washed with water, then brine, filtered and evaporated through fluorosil -Na ₂ SO _4, to give an orange oil (3.5 g). The product was distilled at the beginning (boiling point 160 to 170 ° C. at 0.1 mmHg), then chromatographed on silica gel _{(CCl 4: CHCl 3/1} : 1) was purified by to give the title compound as a light yellow oil It was. The oil gradually crystallized to give a white waxy solid (2.3 g, 59%).
Analytical: Calculated for C ₂₃ H ₃₄ OSSi: C 71.44; H 8.86; S 8.29. Found: C 71.14; H 8.86; S 7.98.

2,6−ジ−ｔ−ブチル−４−メルカプトフェノール(2.4ｇ、10ミリモル)、炭酸カリウム(1.4ｇ、10ミリモル）、およびジメチルアセトアミド(50ml）を混合しそしてアルゴン雰囲気下室温で撹拌した。クロロメチルトリメチルシラン(1.3ｇ、10ミリモル）を、加えそして一夜撹拌した。蒸気浴上で２時間加温し、冷却しそして水でうすめた。エチルエーテルで抽出し、乾燥し、蒸発して明るい黄色の固体（2.8ｇ）を得そして再結晶（CH₃CN）して、標記化合物1.1ｇ（34％）を得た。融点100〜101℃。
分析値：C₁₈H₃₂OSSiに対する計算値：C 66.60; H 9.88; S 9.88。 実測値：C 66.83; H 10.05; S 9.91。 Example 2
2,6-Di-t-butyl-4-[(trimethylsilyl) methylthio] phenol (MDL 28,235)

2,6-Di-tert-butyl-4-mercaptophenol (2.4 g, 10 mmol), potassium carbonate (1.4 g, 10 mmol), and dimethylacetamide (50 ml) were mixed and stirred at room temperature under an argon atmosphere. Chloromethyltrimethylsilane (1.3 g, 10 mmol) was added and stirred overnight. Warm on a steam bath for 2 hours, cool and dilute with water. Extraction with ethyl ether, drying and evaporation gave a light yellow solid (2.8 g) and recrystallization (CH ₃ CN) to give 1.1 g (34%) of the title compound. Mp 100-101 ° C.
Analytical: Calculated for C ₁₈ H ₃₂ OSSi: C 66.60; H 9.88; S 9.88. Found: C 66.83; H 10.05; S 9.91.

2,6−ジメチルヒドロキノン(1.4ｇ、10ミリモル）、炭酸カリウム（1.4ｇ、10ミリモル）、クロロメチルトリメチルシラン（1.9ｇ、10ミリモル）およびジメチルホルムアミド（50ml）を、混合した。反応が完了するまで、不活性雰囲気下室温で撹拌した。混合物を、氷水でうすめそしてエチルエーテルで抽出した。エーテル層を、水、それからブラインで洗浄しそしてフルオロシル−Na₂SO₄を通して濾過した。蒸発して標記化合物を得そしてシリカゲルクロマトグラフィーによって精製した。 Example 3
2,6-Dimethyl-4-[(trimethylsilyl) methyloxy] phenol

2,6-Dimethylhydroquinone (1.4 g, 10 mmol), potassium carbonate (1.4 g, 10 mmol), chloromethyltrimethylsilane (1.9 g, 10 mmol) and dimethylformamide (50 ml) were mixed. Stir at room temperature under an inert atmosphere until the reaction is complete. The mixture was diluted with ice water and extracted with ethyl ether. The ether layer was washed with water, then washed with brine and filtered through fluorosil -Na ₂ SO _4. Evaporation gave the title compound and was purified by silica gel chromatography.

アセトニトリル（200ml）中の2,6−ジ−ｔ−ブチルベンズヒドロキノン（13.7ｇ、61.6ミリモル）、炭酸カリウム（9.4ｇ、68ミリモル)、クロロメチル(４−クロロフェニル）ジメチルシラン(14.9ｇ、68ミリモル）および触媒量の沃化カリウムを、N₂下で３日間還流した。固体を濾去しそして蒸発した。酢酸エチルに再溶解しそして水、それからブラインで洗浄し、無水の硫酸マグネシウムで乾燥し、濾過しそして蒸発した。得られたオレンジ色の油は、0.1mmHgにおいて135℃まで蒸溜して低沸点不純物を除去し次いで生成物(0.1mmHgで沸点℃）を蒸溜することにより精製することができる。放置によって結晶化した生成物を、ヘキサンから再結晶して、微細な白色の針状物質(7.4ｇ、収率27％）を得ることができる。融点102〜105℃。
分析値：C₂₃H₃₃ClO₂Siに対する計算値：C 68.20; H 8.21。 実測値：C68.39; H 8.13。
NMR (CDCl₃): 7.53(d,2H,J 8.3), 7.34(d,2H,J 8.3), 6.79(s,2H),4.73(s,1H), 3.71(s,2H), 1.42(s,18H), 0.41(s,6H) Example 4
2,6-Di-tert-butyl-4-[(4-chlorophenyldimethylsilyl) methyloxy] phenol (MDL 104,280)

2,6-di-tert-butylbenzhydroquinone (13.7 g, 61.6 mmol), potassium carbonate (9.4 g, 68 mmol), chloromethyl (4-chlorophenyl) dimethylsilane (14.9 g, 68 mmol) in acetonitrile (200 ml) ) And a catalytic amount of potassium iodide was refluxed under N ₂ for 3 days. The solid was filtered off and evaporated. Redissolved in ethyl acetate and washed with water, then brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting orange oil can be purified by distilling to 135 ° C. at 0.1 mm Hg to remove low boiling impurities and then distilling the product (boiling point at 0.1 mm Hg). The product crystallized on standing can be recrystallized from hexane to give fine white needles (7.4 g, 27% yield). Mp 102-105 ° C.
Analytical: Calculated for C ₂₃ H ₃₃ ClO ₂ Si: C 68.20; H 8.21. Found: C68.39; H 8.13.
NMR (CDCl ₃ ): 7.53 (d, 2H, J 8.3), 7.34 (d, 2H, J 8.3), 6.79 (s, 2H), 4.73 (s, 1H), 3.71 (s, 2H), 1.42 (s , 18H), 0.41 (s, 6H)

アセトニトリル（150ml）中の2,6−ジ−ｔ−ブチルベンズヒドロキノン（10.0ｇ、45ミリモル）、炭酸カリウム（6.2ｇ、45ミリモル)、およびジメチル（４−フルオロフェニル）ヨードメチルシラン（13.2ｇ、45ミリモル）を、窒素下で３日間還流した。固体を濾去しそして蒸発した。酢酸エチルに再溶解しそして水、それからブラインで洗浄し、無水の硫酸マグネシウムで乾燥し、濾過しそして蒸発して非常に淡黄色の油を得た。この油は放置によって結晶化する。この物質を、メタノールから再結晶して、白色の結晶性の固体（5.9ｇ、収率34％）を得ることができた。融点90〜93℃。
分析値：C₂₃H₃₃FO₂Siに対する計算値：C 71.09; H 8.86。 実測値：C70.96; H 8.58。
NMR (CDCl₃)：7.58(dd,2H,J 8.5, 6.2), 7.10-7.04(m,2H), 6.80(s,2H),4.73(s,1H), 3.71(si,2H), 1.43(s,18H), 0.41(s,6H) Example 5
2,6-di-t-butyl-4-[(dimethyl-4-fluorophenylsilyl) methyloxy] phenol (MDL 104,389)

2,6-Di-tert-butylbenzhydroquinone (10.0 g, 45 mmol), potassium carbonate (6.2 g, 45 mmol), and dimethyl (4-fluorophenyl) iodomethylsilane (13.2 g, 150 ml) in acetonitrile (150 ml). 45 mmol) was refluxed under nitrogen for 3 days. The solid was filtered off and evaporated. Redissolved in ethyl acetate and washed with water then brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give a very pale yellow oil. This oil crystallizes upon standing. This material could be recrystallized from methanol to give a white crystalline solid (5.9 g, 34% yield). Melting point 90-93 ° C.
Analytical: Calculated for C ₂₃ H ₃₃ FO ₂ Si: C 71.09; H 8.86. Found: C70.96; H 8.58.
NMR (CDCl ₃ ): 7.58 (dd, 2H, J 8.5, 6.2), 7.10-7.04 (m, 2H), 6.80 (s, 2H), 4.73 (s, 1H), 3.71 (si, 2H), 1.43 ( s, 18H), 0.41 (s, 6H)

アセトニトリル（125ml）中の2,6−ジ−ｔ−ブチルベンズヒドロキノン（5.43ｇ、24.4ミリモル）、炭酸カリウム（3.7ｇ、26.8ミリモル)およびジメチル(ヨードメチル）フェニルシラン（7.4ｇ、26.8ミリモル）を、N₂下で一夜還流した。固体を濾去しそして蒸発した。酢酸エチルに再溶解しそして水、それからブラインで洗浄し、無水の硫酸マグネシウムで乾燥し、濾過しそして蒸発した。得られたオレンジ色の油は、0.1mmHgにおいて135℃まで蒸溜して低沸点不純物を除去し次いで生成物(0.1mmHgにおいて沸点155〜165℃）を蒸溜することによって精製することができる。放置によって結晶化した生成物は、メタノールから再結晶して白色の固体(5.8ｇ、収率64％）を得ることができる。融点82〜83℃、
分析値：C₂₃H₃₄O₂Siに対する計算値：C 74.54; H 9.25。実測値：C74.51; H 9.28。
NMR (CDCl₃)：7.64-7.58(m,2H), 7.42-7.32(m,2H), 6.80(s,2H), 4.72(s,1H), 3.73(s,2H), 1.42(s,18H), 0.42(s,6H) Example 6
2,6-Di-t-butyl-4-[(dimethylphenylsilyl) methyloxy] phenol (MDL 103,902)

2,6-Di-tert-butylbenzhydroquinone (5.43 g, 24.4 mmol), potassium carbonate (3.7 g, 26.8 mmol) and dimethyl (iodomethyl) phenylsilane (7.4 g, 26.8 mmol) in acetonitrile (125 ml) It was refluxed overnight under N _2. The solid was filtered off and evaporated. Redissolved in ethyl acetate and washed with water, then brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting orange oil can be purified by distilling to 135 ° C. at 0.1 mm Hg to remove low boiling impurities and then distilling the product (boiling point 155-165 ° C. at 0.1 mm Hg). The product crystallized on standing can be recrystallized from methanol to give a white solid (5.8 g, 64% yield). Melting point 82-83 ° C,
Analytical value: Calculated for C ₂₃ H ₃₄ O ₂ Si: C 74.54; H 9.25. Found: C74.51; H 9.28.
NMR (CDCl ₃ ): 7.64-7.58 (m, 2H), 7.42-7.32 (m, 2H), 6.80 (s, 2H), 4.72 (s, 1H), 3.73 (s, 2H), 1.42 (s, 18H ), 0.42 (s, 6H)

アセトニトリル（200ml）中の2,6−ジ−ｔ−ブチルベンズヒドロキノン（13.7ｇ、61.1ミリモル）、炭酸カリウム（9.4ｇ、68ミリモル)、クロロメチル(ジメチル）−４−メトキシフェニルシラン（14.6ｇ、68ミリモル）および触媒量の沃化カリウムを、N₂下で３日間還流した。固体を濾去しそして蒸発した。酢酸エチルに再溶解しそして水、それからブラインで洗浄し、無水の硫酸マグネシウムで乾燥し、濾過しそして蒸発した。得られたオレンジ色の油は、0.1mmHgにおいて135℃まで蒸溜して低沸点の不純物を除去し次いで生成物(0.1mmHgにおいて沸点155〜165℃）を蒸溜することによって精製することができる。放置によって結晶化した生成物を、ヘキサンから再結晶して白色の固体（4.9ｇ、収率19％）を得ることができる。融点122〜123℃。
分析値：C₂₄H₃₆O₃Siに対する計算値：C 71.95; H 9.06。 実測値：C71.80; H 9.00。
NMR (CDCl₃)：7.53(d,2H,J 8.6), 6.93(d,2H,J 8.6), 6.80(s,2H),4.71(s,1H), 3.81(s,3H), 3.70(s,2H), 1.42(s,18H), 0.39(s,6H) Example 7
2,6-Di-tert-butyl-4-[(dimethyl-4-methoxyphenylsilyl) methyloxy] phenol (MDL 105,074)

2,6-di-tert-butylbenzhydroquinone (13.7 g, 61.1 mmol), potassium carbonate (9.4 g, 68 mmol), chloromethyl (dimethyl) -4-methoxyphenylsilane (14.6 g, acetonitrile in 200 ml) 68 mmol) and a catalytic amount of potassium iodide were refluxed under N ₂ for 3 days. The solid was filtered off and evaporated. Redissolved in ethyl acetate and washed with water, then brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting orange oil can be purified by distilling to 135 ° C. at 0.1 mm Hg to remove low boiling impurities and then distilling the product (boiling point 155-165 ° C. at 0.1 mm Hg). The product crystallized on standing can be recrystallized from hexane to give a white solid (4.9 g, 19% yield). Melting point 122-123 ° C.
Analytical: Calculated for C ₂₄ H ₃₆ O ₃ Si: C 71.95; H 9.06. Found: C71.80; H 9.00.
NMR (CDCl ₃ ): 7.53 (d, 2H, J 8.6), 6.93 (d, 2H, J 8.6), 6.80 (s, 2H), 4.71 (s, 1H), 3.81 (s, 3H), 3.70 (s , 2H), 1.42 (s, 18H), 0.39 (s, 6H)

アセトニトリル(150ml）中の2,6−ジメチルヒドロキノン(10.0ｇ、72.4ミリモル）、炭酸カリウム（10.0ｇ、72.4ミリモル）およびジメチル（クロロメチル）フェニルシラン（13.4ｇ、72.4ミリモル）を、アルゴン下で72時間還流した。混合物を、冷却しそして水でうすめそしてエーテルで抽出した。油を、0.1mmHgにおいて145〜160℃で蒸溜して明るい黄色の油4.9ｇを得た。
分析値：C₁₇H₂₂O₂Siに対する計算値：C 71.28; H 7.74。 実測値：C71.27; H 7.74。 Example 8
2,6-Dimethyl-4-[(dimethylphenylsilyl) methyloxy] phenol (MDL 103,719)

2,6-Dimethylhydroquinone (10.0 g, 72.4 mmol), potassium carbonate (10.0 g, 72.4 mmol) and dimethyl (chloromethyl) phenylsilane (13.4 g, 72.4 mmol) in acetonitrile (150 ml) were added under argon. Reflux for hours. The mixture was cooled and diluted with water and extracted with ether. The oil was distilled at 145-160 ° C. at 0.1 mm Hg to give 4.9 g of a bright yellow oil.
Analytical: Calculated for C ₁₇ H ₂₂ O ₂ Si: C 71.28; H 7.74. Found: C71.27; H 7.74.

イソプロパノール（150ml）中の２−ｔ−ブチル−６−メチル−４−メルカプトフェノール（11.8ｇ、60.1ミリモル）、重炭酸カリウム（6.0ｇ、11.8ミリモル）およびジメチル（クロロメチル）フェニルシラン（11.1ｇ、60.1ミリモル）を、アルゴン下で24時間還流した。混合物を、冷却しそして水でうすめそしてエーテルで抽出した。エーテル層を、蒸発乾固して油21.9ｇを得た。この油を145〜160℃(0.1mmHg）で蒸溜して、明るい黄色の油5.5ｇを得た。
分析値：C₂₀H₂₈OSSiに対する計算値：C 69.71; H 8.19。 実測値：C69.76; H 8.20。 Example 9
2-t-butyl-6-methyl-4-[(dimethylphenylsilyl) methylthio] phenol (MDL 104,518)

2-tert-butyl-6-methyl-4-mercaptophenol (11.8 g, 60.1 mmol), potassium bicarbonate (6.0 g, 11.8 mmol) and dimethyl (chloromethyl) phenylsilane (11.1 g, isopropanol (150 ml). 60.1 mmol) was refluxed under argon for 24 hours. The mixture was cooled and diluted with water and extracted with ether. The ether layer was evaporated to dryness to give 21.9 g of oil. This oil was distilled at 145-160 ° C. (0.1 mm Hg) to give 5.5 g of a bright yellow oil.
Analytical: Calculated for C ₂₀ H ₂₈ OSSi: C 69.71; H 8.19. Found: C69.76; H 8.20.

クロロメチルジメチル(２−メトキシ）フェニルシラン（27.2ｇ、0.127モル）、沃化ナトリウム(19ｇ、0.127モル）およびアセトニトリル(350ml）の混合物を、28時間加熱還流した。混合物を周囲温度に冷却しそして2,6−ジ−ｔ−ブチル−1,4−ヒドロキノン(31.5ｇ、0.14モル）および炭酸カリウム（20.8ｇ、0.15モル）を加えた。混合物を、窒素雰囲気下で７日間還流した。混合物を冷却し、水（400ml）および酢酸エチル（400ml）に注加しそして有機層を分離した。有機層を蒸発しそして残留物をシリカゲル上でクロマトグラフィー処理（９／１のヘキサン／酢酸エチル）した。クロマトグラフィー処理した生成物を、メタノールから再結晶して、白色の固体として生成物（15.6ｇ、31％）を得た。
分析値：C₂₄H₃₆O₃Siに対する計算値：C 71.95; H 9.06。 実測値：C71.84; H 9.05。 Example 10
2,6-Di-tert-butyl-4-[(dimethyl-2-methoxyphenylsilyl) methyloxy] phenol (MDL 104,036)

A mixture of chloromethyldimethyl (2-methoxy) phenylsilane (27.2 g, 0.127 mol), sodium iodide (19 g, 0.127 mol) and acetonitrile (350 ml) was heated to reflux for 28 hours. The mixture was cooled to ambient temperature and 2,6-di-tert-butyl-1,4-hydroquinone (31.5 g, 0.14 mol) and potassium carbonate (20.8 g, 0.15 mol) were added. The mixture was refluxed for 7 days under a nitrogen atmosphere. The mixture was cooled, poured into water (400 ml) and ethyl acetate (400 ml) and the organic layer was separated. The organic layer was evaporated and the residue was chromatographed on silica gel (9/1 hexane / ethyl acetate). The chromatographed product was recrystallized from methanol to give the product (15.6 g, 31%) as a white solid.
Analytical: Calculated for C ₂₄ H ₃₆ O ₃ Si: C 71.95; H 9.06. Found: C71.84; H 9.05.

シランとしてクロロメチルジメチル−2.5−ジメトキシ−フェニルシラン（14ｇ、57ミリモル）を使用して上記化合物に対すると同様にして製造して、白色の固体を得た。融点103〜104℃
分析値：C₂₅H₃₈O₄Siに対する計算値：C 69.72; H 8.89。 実測値：C69.71; H 8.72。 Example 11
2,6-di-tert-butyl-4-[(dimethyl-2.5-dimethoxyphenylsilyl) methyloxy] phenol (MDL 103,016)

Prepared as above for the above compound using chloromethyldimethyl-2.5-dimethoxy-phenylsilane (14 g, 57 mmol) as silane to give a white solid. Melting point 103-104 ° C
Analytical: Calculated for C ₂₅ H ₃₈ O ₄ Si: C 69.72; H 8.89. Found: C69.71; H 8.72.

シランとしてクロロメチル(ジメチル）−2,3−ジメトキシフェニルシラン（11.3ｇ、46ミリモル）を使用して上述したようにして製造して、白色の固体を得た。融点94.5〜96℃
分析値：C₂₅H₃₈O₄Siに対する計算値：C 69.72; H 8.89。 実測値：C69.84; H 8.91。 Example 12
2,6-Di-tert-butyl-4-[(dimethyl-2,3-dimethoxyphenylsilyl) methyloxy] phenol (MDL 108,750)

Prepared as described above using chloromethyl (dimethyl) -2,3-dimethoxyphenylsilane (11.3 g, 46 mmol) as silane to give a white solid. Melting point 94.5 ~ 96 ℃
Analytical: Calculated for C ₂₅ H ₃₈ O ₄ Si: C 69.72; H 8.89. Found: C69.84; H 8.91.

シランとして４−ｔ−ブチルフェニルクロロメチルジメチルシラン(6.2ｇ、25.7ミリモル）を使用して上述したようにして製造して、白色の固体として生成物を得た。融点114〜115℃
分析値：C₂₇H₄₂O₂Siに対する計算値：C 76.00; H 9.92。実測値：C75.94; H 10.13。 Example 13
2,6-Di-tert-butyl-4-[(dimethyl-4-tert-butylphenylsilyl) methyloxy] phenol (MDL 106,630)

Prepared as described above using 4-t-butylphenylchloromethyldimethylsilane (6.2 g, 25.7 mmol) as the silane to give the product as a white solid. Melting point 114-115 ° C
Analytical value: Calculated for C ₂₇ H ₄₂ O ₂ Si: C 76.00; H 9.92. Found: C75.94; H 10.13.

シランとしてベンジルクロロメチルジメチルシラン（7.13ｇ、35.9ミリモル）を使用して上述したようにして製造して、白色の固体として生成物を得た。融点76〜77℃
分析値：C₂₄H₃₆O₂Siに対する計算値：C 74.95; H 9.43。実測値：C74.94; H 9.36。 Example 14
2,6-Di-t-butyl-4-[(benzyldimethylsilyl) methyloxy] phenol (MDL 107,411)

Prepared as described above using benzylchloromethyldimethylsilane (7.13 g, 35.9 mmol) as silane to give the product as a white solid. Melting point 76-77 ° C
Analytical: Calculated for C ₂₄ H ₃₆ O ₂ Si: C 74.95; H 9.43. Found: C74.94; H 9.36.

工程ａ：ジメチル−ｐ−メトキシベンジル−クロロメチルシランの製造
マグネシウム片（9.7ｇ、0,4グラム原子）を、テフロン^(R)パドルを使用して、窒素下で一夜撹拌した。この“活性化された”マグネシウムを乾燥THF（100ml）に懸濁しそして沃素の結晶を加えた。おだやかな還流を維持するような速度で、この懸濁液に、THF（400ml）中のｐ−メトキシベンジルブロマイド(80.8ｇ、0.4モル）の溶液を加えた。添加完了時に、殆どすべてのマグネシウムが消費されるまで、撹拌をつづけた(〜２時間）。THF（200ml）中のジメチルクロロメチルクロロシラン（52.7ml、0.4モル）の溶液を、滴加しそして混合物を、室温で一夜撹拌した。反応混合物を飽和水性塩化アンモニウム(500ml）でクエンチしそして室温で撹拌(〜２時間)した。沈殿したマグネシウム塩を濾過しそしてエーテル(300ml）でうすめた。有機相を分離し、水(３×250ml）、飽和水性塩化ナトリウム(３×250ml)で洗浄し、無水の硫酸マグネシウムで乾燥し、濾過しそして蒸発した。得られた褐色の油を蒸溜によって精製して標記化合物を得た。収率55％。沸点５mmHgにおいて110〜115℃
分析値：C₁₀H₁₅ClOSiに対する計算値：C 55.93; H 7.15。実測値：C55.40; H 7.15。 Example 15
2,6-Di-t-butyl-4-[(dimethyl-p-methoxybenzylsilyl) methyloxy] phenol (MDL 108,816)

Step a: Dimethyl -p- methoxybenzyl - producing magnesium turnings chloromethyl silane (9.7 g, 0, 4 gram atom) was converted, using Teflon ^(R) paddle, and stirred overnight under nitrogen. The “activated” magnesium was suspended in dry THF (100 ml) and iodine crystals were added. To this suspension was added a solution of p-methoxybenzyl bromide (80.8 g, 0.4 mol) in THF (400 ml) at such a rate as to maintain a gentle reflux. Upon completion of the addition, stirring was continued until almost all of the magnesium was consumed (~ 2 hours). A solution of dimethylchloromethylchlorosilane (52.7 ml, 0.4 mol) in THF (200 ml) was added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride (500 ml) and stirred at room temperature (˜2 hours). The precipitated magnesium salt was filtered and diluted with ether (300 ml). The organic phase was separated, washed with water (3 × 250 ml), saturated aqueous sodium chloride (3 × 250 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting brown oil was purified by distillation to give the title compound. Yield 55%. 110-115 ° C at a boiling point of 5 mmHg
Analytical: Calculated for C ₁₀ H ₁₅ ClOSi: C 55.93; H 7.15. Found: C55.40; H 7.15.

Step b: Preparation of 2,6-di-t-butyl-4-[(dimethyl-p-methoxybenzylsilyl) methyloxy] phenol (MDL 108,816) Dimethyl-p-methoxybenzyl-chloromethyl in acetonitrile (250 ml) A mixture of silane (28 g, 0.13 mol), sodium iodide (0.5 g, catalytic amount), 2,6-di-tert-butylbenzhydroquinone (23 g, 0.1 mol) and cesium carbonate (32 g, 0.1 mol) was refluxed. Heated under 6 days, cooled and poured into a mixture of water / ethyl acetate (400 ml each). The organic layer was isolated, dried, evaporated and the residue was heated in a Kugelrohr apparatus at 110 ° C. (0.1 mm) for 3 hours and 140-160 ° C. for a further 2 hours. The residue was solidified by standing to give the product (20.9 g, 39%) as a waxy solid. Melting point 58-60 ° C
Analytical: Calculated for C ₂₅ H ₃₈ O ₃ Si: C 72.41; H 8.87. Found: C70.29; H 8.96.

The following compounds can be produced by operations similar to those described above in Examples 1-14.
2,6-Di-tert-butyl-4-[(triethylsilyl) methylthio] phenol
2,6-Di-tert-butyl-4-[(diethylphenylsilyl) methylthio] phenol
2,6-Di-t-butyl-4-[(tripropylsilyl) methylthio] phenol
2,6-Di-t-butyl-4-[(dipropylphenylsilyl) methylthio] phenol
2,6-Di-tert-butyl-4-[(triisopropylsilyl) methylthio] phenol
2,6-Di-t-butyl-4-[(diisopropylphenylsilyl) methylthio] phenol
2,6-Di-tert-butyl-4-[(tributylsilyl) methylthio] phenol
2,6-Di-t-butyl-4-[(dibutylphenylsilyl) methylthio] phenol
2,6-Di-tert-butyl-4-[(triisobutylsilyl) methylthio] phenol
2,6-Di-t-butyl-4-[(diisobutylphenylsilyl) methylthio] phenol
2,6-Di-tert-butyl-4-[(tri-tert-butylsilyl) methylthio] phenol
2,6-Di-tert-butyl-4-[(di-tert-butylphenylsilyl) methylthio] phenol

2,6-Di-methyl-4-[(trimethylsilyl) methylthio] phenol
2,6-Di-methyl-4-[(dimethylphenylsilyl) methylthio] phenol
2,6-Di-methyl-4-[(dibutylphenylsilyl) methylthio] phenol
2,6-Di-methyl-4-[(tri-t-butylsilyl) methylthio] phenol
2,6-Di-methyl-4-[(di-t-butylphenylsilyl) methylthio] phenol
2,6-Di-ethyl-4-[(trimethylsilyl) methylthio] phenol
2,6-Di-ethyl-4-[(dimethylphenylsilyl) methylthio] phenol
2,6-Di-ethyl-4-[(tri-t-butylsilyl) methylthio] phenol
2,6-Di-ethyl-4-[(di-t-butylphenylsilyl) methylthio] phenol
2,6-Di-propyl-4-[(trimethylsilyl) methylthio] phenol

2,6-Di-propyl-4-[(dimethylphenylsilyl) methylthio] phenol
2,6-Di-isopropyl-4-[(trimethylsilyl) methylthio] phenol
2,6-Di-isopropyl-4-[(dimethylphenylsilyl) methylthio] phenol
2,6-Di-butyl-4-[(trimethylsilyl) methylthio] phenol
2,6-Di-butyl-4-[(dimethylphenylsilyl) methylthio] phenol
2,6-Dimethyl-4-[(trimethylsilyl) methyloxy] phenol
2,6-Dimethyl-4-[(dimethylphenylsilyl) methyloxy] phenol
2,6-Dibutyl-4-[(triethylsilyl) methyloxy] phenol
2,6-Dibutyl-4-[(diethylphenylsilyl) methyloxy] phenol
2,6-Di-tert-butyl-4-[(trimethylsilyl) methyloxy] phenol
2,6-di-tert-butyl-4-[(dimethylphenylsilyl) methyloxy] phenol.

The general synthetic scheme for preparing compounds of Formula 1 where Z is methylene is as described in Scheme B. Unless otherwise stated, all substitutions are as described above.

  In general, the phenol of structure 1b can be prepared according to Scheme B in a two-step process. In step a, a suitable haloalkylenesilane of structure 3 is reacted with magnesium metal in a suitable aprotic solvent such as ethyl ether to form a magnesium halide salt. The magnesium halide salt (Grignard reagent) is then reacted with the appropriate 3,5-dialkyl-4-hydroxy-benzaldehyde of structure 4 (or an appropriately protected derivative) to give the alcohol of structure 5. In step b, the alcohol of structure 5 can be reduced to obtain the desired phenol of structure 1b by various reduction techniques and procedures well known and recognized in the art. For example, an alcohol of structure 5 can be reduced by Birch reduction by reacting it with sodium in liquid ammonia.

The starting materials used in the general synthetic procedure described in Scheme B are readily available or can be readily prepared by standard techniques and procedures. If it is necessary to prevent unwanted side reactions, the 1-phenol functionality of 3,5-dialkyl-4-hydroxy-benzaldehyde of structure 4 in Scheme B was as described above in Scheme A prior to the Grignard reaction. It can be blocked with such standard phenol blocking agents.
The following examples show typical syntheses as described in Scheme B. It should be understood that this example is illustrative only and does not limit the scope of the invention in any way.

工程ａ： マグネシウム片（240mg、10ミリモル）および無水のエチルエーテルを、不活性雰囲気下で混合した。無水のエチルエーテル中のクロロメチルトリメチルシラン(1.9ｇ、10ミリモル）の溶液を加える。マグネシウム金属が溶解するまで撹拌した。無水のエチルエーテル中の3,5−ジメチル−４−ヒドロキシベンズアルデヒド(1.5ｇ、10ミリモル）の溶液を加えた。反応が完了するまで撹拌した。反応混合物を、０℃に冷却しそして飽和塩化アンモニウム溶液を加えた。エーテル層を分離し、水で洗浄しそして乾燥（MgSO₄）する。蒸発して４−ヒドロキシ−3,5−ジメチル−α−〔（トリメチルシリル）メチル〕ベンゼンメタノールを得そしてシリカゲルクロマトグラフィーによって精製した。 Example 16
2,6-Dimethyl-4- [2- (trimethylsilyl) ethyl] phenol

Step a: Magnesium pieces (240 mg, 10 mmol) and anhydrous ethyl ether were mixed under an inert atmosphere. A solution of chloromethyltrimethylsilane (1.9 g, 10 mmol) in anhydrous ethyl ether is added. Stir until the magnesium metal is dissolved. A solution of 3,5-dimethyl-4-hydroxybenzaldehyde (1.5 g, 10 mmol) in anhydrous ethyl ether was added. Stir until the reaction is complete. The reaction mixture was cooled to 0 ° C. and saturated ammonium chloride solution was added. The ether layer is separated, washed with water and dried (MgSO ₄ ). Evaporation gave 4-hydroxy-3,5-dimethyl-α-[(trimethylsilyl) methyl] benzenemethanol and was purified by silica gel chromatography.

Step b: Sodium metal (520 mg, 22.6 mmol) and liquid ammonia (13 ml) were mixed. To this solution was added dropwise a solution of 4-hydroxy-3,5-dimethyl-α-[(trimethylsilyl) -methyl] benzenemethanol (2.22 g, 10 mmol) in ethyl alcohol (0.5 g) and ethyl ether (5 ml). Add. After the blue color disappeared, water (13 ml) was carefully added, extracted with ethyl ether, dried (MgSO ₄ ) and the solvent evaporated. The residue was purified by silica gel chromatography to give the title compound.
Instead of as described above, compounds of formula (1) wherein Z is methylene can be prepared by the procedure described in Scheme C. In Scheme C, all substituents are as described above unless otherwise stated.

  In general, the phenol of structure 1b can be prepared by first reacting a suitable haloalkylene silane of structure 3 with magnesium metal to form a magnesium halide salt in a suitable aprotic solvent such as ethyl ether. it can. The magnesium halide salt (Grignard reagent) is then reacted with the appropriate 3,5-dialkyl-4-hydroxy-benzyl halide (or appropriately protected derivative) of structure 6 to give the desired phenol of structure 1b.

The starting materials used in the general synthetic procedure described in Scheme C are readily available or can be readily prepared by standard techniques and procedures. For example, the preparation of 3,5-dimethyl-4-acetoxy-benzyl bromide is described in Tetrahedron 33, 3097-103 (1977). 3,5-Dimethyl-4-acetoxy-benzyl bromide can be converted to the corresponding phenol starting material by standard hydrolysis procedures.

If it is necessary to prevent unwanted side reactions, the 1-phenol function of the 3,5-dialkyl-4-hydroxy-benzyl halide of structure 6 in Scheme C is as described above in Scheme A prior to the Grignard reaction. Can be blocked with standard phenol blocking agents.
The following example illustrates a typical synthesis as described in Scheme C. It should be understood that this example is illustrative only and does not limit the scope of the invention in any way.

マグネシウム片（240mg、10ミリモル）および無水のエチルエーテルを、不活性雰囲気下で混合した。無水のエチルエーテル中のクロロメチルトリメチルシラン(1.9ｇ、10ミリモル）の溶液を加えた。マグネシウム金属が溶解するまで、撹拌した。無水のエチルエーテル中の４−ブロモメチル−2,6−ジエチルフェノール(2.43ｇ、10ミリモル）の溶液を加えそして混合物を、反応が完了するまで、還流した。氷／塩酸の混合物に注加しそして層を分離した。エーテル層を水で洗浄し、乾燥(MgSO₄）しそして蒸発して標記化合物を得た。これを、シリカゲルクロマトグラフィーによって精製した。 Example 17
2,6-Diethyl-4- [2- (trimethylsilyl) ethyl] phenol

Magnesium pieces (240 mg, 10 mmol) and anhydrous ethyl ether were mixed under an inert atmosphere. A solution of chloromethyltrimethylsilane (1.9 g, 10 mmol) in anhydrous ethyl ether was added. Stir until the magnesium metal is dissolved. A solution of 4-bromomethyl-2,6-diethylphenol (2.43 g, 10 mmol) in anhydrous ethyl ether was added and the mixture was refluxed until the reaction was complete. Pour into an ice / hydrochloric acid mixture and separate the layers. The ether layer was washed with water, dried (MgSO ₄ ) and evaporated to give the title compound. This was purified by silica gel chromatography.

The following compounds can be prepared by operations similar to those described above in Example 16.
2,6-Dipropyl-4- [2- (trimethylsilyl) ethyl] phenol
2,6-Dipropyl-4- [2- (dimethylphenylsilyl) ethyl] phenol
2,6-Diisopropyl-4- [2- (trimethylsilyl) ethyl] phenol
2,6-Diisopropyl-4- [2- (dimethylphenylsilyl) ethyl] phenol
2,6-Diisobutyl-4- [2- (trimethylsilyl) ethyl] phenol
2,6-Diisobutyl-4- [2- (dimethylphenylsilyl) ethyl] phenol
2,6-Dibutyl-4- [2- (trimethylsilyl) ethyl] phenol
2,6-Dibutyl-4- [2- (dimethylphenylsilyl) ethyl] phenol
2,6-Di-tert-butyl-4- [2- (trimethylsilyl) ethyl] phenol
2,6-Di-t-butyl-4- [2- (dimethylphenylsilyl) ethyl] phenol
2,6-Di-tert-butyl-4- [2- (tri-tert-butylsilyl) ethyl] phenol
2,6-Di-tert-butyl-4- [2- (di-tert-butylphenylsilyl) ethyl] phenol
2,6-Dimethyl-4- [2- (trimethylsilyl) ethyl] phenol
2,6-Dimethyl-4- [2- (dimethylphenylsilyl) ethyl] phenol

  It should be understood that the compound of formula (1) can exist in various stereoisomeric forms. All stereoisomeric forms consistent with the above structural formula as interpreted by standard practice for representing stereoisomeric structures are intended to be included within the scope of the present invention.

Compounds of formula (1), such as 2,6-dialkyl-4-silyl-phenol, are known in the art. In particular, compounds of formula (1) are described in US Pat. No. 5,155,250. R ₁ and R ₂ are C ₄ alkyl groups, R ₃ and R ₄ are C ₁ alkyl groups, A is a C ₁ alkylene group, and R ₅ is — (CH ₂ ) _n — (Ar) (formula In which n is 0 and Ar is unsubstituted or substituted by ₁ to 3 substituents selected from the group consisting of hydroxy, methoxy, ethoxy, chlorine, fluorine or C ₁ -C ₆ alkyl Compounds of formula (1) are preferred. The compound 2,6-di-t-butyl-4-[(dimethylphenylsilyl) methyl] -thio-phenol is more preferred.

  As used herein, the term “patient” refers to a warm-blooded animal or mammal suffering from a particular VCAM-1-mediated inflammatory disease. It should be understood that guinea pigs, including humans, dogs, cats, rats, mice, hamsters, rabbits and primates are examples of patients within the meaning of this term.

  The term “chronic inflammatory disease” refers to a disease or condition characterized by persistent inflammation in the absence of an irritant or microbial pathogen that can be identified. Inflammatory diseases for which treatment with compounds of formula (1) are particularly useful include asthma, chronic inflammation, rheumatoid arthritis, autoimmune diabetes, transplant tissue rejection and tumor angiogenesis. Particularly preferred compounds of formula (1) for the treatment of inflammatory diseases in patients in need of treatment include the following compounds:

2,6-di-t-butyl-4-[(dimethylphenylsilyl) methylthio] phenol;
2,6-di-t-butyl-4-[(trimethylsilyl) methylthio] phenol;
2,6-di-t-butyl-4-[(4-chlorophenyldimethylsilyl) methyloxy] phenol;
2,6-di-t-butyl-4-[(dimethyl-4-fluorophenylsilyl) methyloxy] phenol;
2,6-di-t-butyl-4-[(dimethylphenylsilyl) methyloxy] phenol;
2,6-di-t-butyl-4-[(dimethyl-4-methoxyphenylsilyl) methyloxy] phenol;
2,6-dimethyl-4-[(dimethylphenylsilyl) methyloxy] phenol;
2-t-butyl-6-methyl-4-[(dimethylphenylsilyl) methylthio] phenol

2,6-di-t-butyl-4-[(dimethyl-2-methoxyphenylsilyl) methyloxy] phenol;
2,6-di-t-butyl-4-[(dimethyl-2,5-dimethoxyphenylsilyl) methyloxy] phenol;
2,6-di-t-butyl-4-[(dimethyl-2,3-dimethoxyphenylsilyl) methyloxy] phenol;
2,6-di-tert-butyl-4-[(dimethyl-4-tert-butylphenylsilyl) methyloxy] phenol; and
2,6-di-t-butyl-4-[(benzyldimethylsilyl) methyloxy] phenol.

  A “therapeutically effective amount” of a compound of formula (1) is an amount effective to provide relief of symptoms associated with inflammatory disease by administration of a single or multiple doses to a patient. An “effective vascular cell adhesion molecule-1 inhibitory amount” of a compound of formula (1) reduces the symptoms associated with a vascular cell adhesion molecule-1 mediated condition by administration of a single or multiple doses to a patient. An effective amount to give. As used herein, symptomatic relief of an inflammatory disease or vascular cell adhesion molecule-1 mediated condition means a reduction in severity over that expected in the absence of treatment, and does not necessarily represent the overall disease It does not indicate removal or healing. Symptom relief also plans to include prevention.

  The determination of a therapeutically effective amount or dose includes, but is not limited to, the type of mammal; its size, age and general health; the specific disease involved; the extent of the disease; Specific factors to be administered; method of administration; bioavailability of the formulation to be administered; selected dosage regimen; concurrent drug use; and other relevant circumstances Is considered by.

  A therapeutically effective amount of a compound of formula (1) is generally between about 1 mg / kg body weight / day (mg / kg / day) to about 5 g / kg body weight / day (g / kg / day). To change. A daily dose of about 1 mg / kg to about 500 mg / kg is preferred. Similarly, an effective vascular cell adhesion molecule-1 inhibitory amount of a compound of formula (1) generally ranges from about 1 mg / kg body weight / day (mg / kg / day) to about 5 g / kg body weight / day (g / Kg / day). A daily dose of about 1 mg / kg to about 500 mg / kg is preferred.

  The compounds of the present invention are inhibitors of VCAM-1 expression. The compounds of the present invention show an inhibitory effect by inhibiting VCAM-1 upregulation by cytokines, thereby preventing or reducing the pathology of inflammatory diseases including asthma, chronic inflammation, rheumatoid arthritis, autoimmune diabetes, etc. I believe it. However, it is to be understood that the invention is not limited by any particular theory or proposed mechanism that explains its effectiveness in end use applications.

  In effective treatment of patients, the compound of formula (1) is any form or method that allows the compound to be used biologically in an effective amount, including oral and parenteral routes. Can be administered. For example, the compounds can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally and in other similar ways. Oral administration is generally preferred. Those skilled in the art of preparing formulations can readily select the appropriate mode of administration and method depending on the disease state being treated, the stage of the disease and other relevant circumstances. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990).

  The compound of formula (1) can be administered in the form of a pharmaceutical composition or medicament prepared by combining the compound of formula (1) with a pharmaceutically acceptable carrier or excipient. The proportions and nature of these compositions are determined by the chosen route of administration and standard pharmaceutical practice.

  The pharmaceutical composition or medicament is produced by methods known in the pharmaceutical art. A carrier or excipient is a solid, semi-solid, or liquid material that can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are known in the art. The pharmaceutical composition can be used orally or parenterally and can be administered to a patient in the form of tablets, capsules, suppositories, solutions, suspensions and the like.

  The pharmaceutical composition can be administered orally, for example with an inert diluent or with an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compound of formula (1) can be mixed with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. . These formulations must contain at least 4% of the compound of formula (1). However, the active ingredient can vary depending on the particular form and usually can be between 4 and about 70% of the weight of the unit. The amount of active ingredient present in the composition is such that a unit dosage form suitable for administration is obtained.

  Tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose Disintegrating agents such as alginic acid, primogel, corn starch and the like; lubricants such as magnesium stearate or sterotex; lubricants such as colloidal silicon dioxide; Or orange flavor. When the dosage unit form is a capsule, it can contain, in addition to a substance of the above type, a liquid carrier such as polyethylene glycol or fatty oil. Other dosage unit forms may contain various other materials that modify the physical form of the dosage unit, such as coatings. That is, the tablets or pills can be coated with sugar, shellac or other enteric coatings. In addition to the active ingredient, syrups can contain sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. The materials used in the manufacture of these various compositions must be pharmaceutically pure and non-toxic in the amounts used.

  For the purpose of parenteral administration, the compound of formula (1) can be incorporated into a solution or suspension. These formulations must contain at least 0.1% of the compound of the invention, but can vary between about 0.1-50% of the weight of the formulation. The amount of active ingredient present in such compositions is such that a suitable dosage will be obtained.

  Solutions or suspensions may also contain one or more of the following adjuvants depending on the solubility and other properties of the compound of formula (1): sterile diluents, eg for injection Water, saline solution, non-volatile oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium acid sulfite; chelating agents such as ethylenediamine Tetraacetic acid; buffers such as acetate, citrate or phosphate and tonicity modifiers such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Example 18
Cell surface ELISA for VCAM-1 / ICAM-1
Proliferated human navel vein endothelial cells (HUVEC) or human aortic smooth muscle cells (HASMC) from Clonetics (San Diego, Calif.) In a medium of 100 μl per well at 20,000 cells per cm ² on 96-well plates. And then plated. Prior to addition of cytokines or drugs, the cultures were maintained in growth medium (EGM or SMGM2, Clonetics, San Diego, CA) for 2 days. Cytokine + or −compounds were added for 20-24 hours prior to analysis for adhesion molecule level. Tumor necrosis factor (Genzyme, Cambridge, MA) was added to the medium at 500-1000 units / ml. Interleukin-4 (GIBCO-BRL, Gaithersburg, MD) was added to the medium at 100-200 pg / ml. (Addition was done by transferring 100 μl of serially diluted cytokine + compound on a separate 96-well plate to the plate containing the cells. Prior to the addition of the effector, the medium for the culture was changed. Not) The medium was removed and the monolayer was washed twice with Hanks buffered salt solution (HBSS) at room temperature. Primary antibody (anti-human VCAM-1 from UpstateBiotechnology Inc., Lake Placid, NY or anti-human ICAM-1 from Immunotech Inc., Westbrook, ME) is added to each well [HBSS + 5% newborn calf serum ( 1 μg / ml in GIBCO-BRL, Gaithersburg, MD) and incubated at 37 ° C. for 1 hour. Wells were washed twice with HBSS and then 100 μl each of 1/1000 dilution of goat anti-mouse IgG (BioRad, Hercules, CA) conjugated to horseradish peroxidase in HBSS + 5% newborn calf serum. And incubated at 37 ° C. for 1 hour. The wells were washed 3 times with HBSS, and then 100 μl of TMB substrate (BioRad, Hercules, CA) was added to each well. The reaction was stopped after a blue color developed by the addition of 50 μl of 1N H ₂ SO ₄ .

Absorbance was measured at 450 nm using a plate reader. IC ₅₀ values were determined from curves of absorbance values obtained from serial dilutions of compounds (dissolved in dimethyl sulfoxide).
IC ₅₀ values are defined as the concentration of drug that inhibits cytokine-induced adhesion molecule expression by 50%. The level of induction was determined by subtracting the highest level of adhesion molecule expression in the cytokine-induced culture from the basal level of adhesion molecule expression in the culture (-cytokine). VCAM-1 was typically induced about 5-7 fold. ICAM-1 was typically induced about 5-10 fold. Each drug concentration was tested in quadruplicate wells. A single point test of the compound at 50 μM was tested as described above for IC ₅₀ values, except that the data show the level of inhibition without correction for basal expression. (Base adhesion molecule expression was 10-20% of the total induced expression).
Table 1 summarizes the ability of various compounds of the present invention to inhibit VCAM-1 when using human aortic smooth muscle cells (HASMC). In these experiments, cells were incubated with interleukin-4 and the compounds shown in the table for about 20 hours before examining cell surface VCAM-1 levels. Each column represents a separate experiment.

  Table 2 summarizes the ability of various compounds of the present invention to selectively inhibit VCAM-1 or both VCAM-1 and ICAM-1 when using proliferating human navel vein endothelial cells (HUVEC). To do. In these experiments, cells were incubated for about 20-24 hours with tumor necrosis factor-α and the compounds shown in the table before examining cell surface adhesion molecule expression.

Table 3 shows the activity of selected compounds when eight serial dilutions of the drug were tested against cytokine induction of VCAM-1 expression in both vascular endothelium and smooth muscle cells. Subtraction of basal VCAM-1 expression was also used in the calculation of IC ₅₀ values. Each compound was also tested in a similar manner for ICAM-1 inhibition. Inhibition against ICAM-1 was not detected in vascular smooth muscle cells (up to 100 μM). In vascular endothelial cells, only MDL103,902 showed significant inhibition of ICAM-1 expression at 50 and 100 μM. This can be explained by the loss of cell adhesion to the tissue culture surface as observed with a microscope.

Example 19
In Vivo Inhibition of VCAM-1 Upregulation by MDL 29,353 in Rabbit Aorta New Zealand White Rabbits with chow + or −0.4% MDL 29,353 diet and lipopolysaccharide (LPS, 40 μg / animal, iv ear vein) Supplied for 3 weeks before the challenge. Each aorta was removed from the animal 4 hours after LPS injection and briefly rinsed with phosphate buffered saline. VCAM-1 was measured immunohistochemically. This was accomplished by incubating the tissue with RB 1/9 antibody (mouse anti-rabbit VCAM-1) overnight at 4 ° C. Bound RB 1/9 was detected using a biotinylated goat anti-mouse secondary antibody (room temperature, 60 min). VCAM-1 staining was achieved by addition of streptavidin-alkaline phosphate complex (30 minutes at room temperature) followed by incubation with BT Red (Biotec, 10, room temperature). Stained tissue images were captured using an image analysis system for the determination of the percentage of aortic endothelium that is immunoreactive with anti-VCAM antibodies.

The in vivo activity of these compounds can also be evaluated in other models of inflammation that are expected to be associated with elevated VCAM-1 levels. One such model for respiratory diseases such as asthma is the ovalbumin-sensitization model. Kung, TT et al . , Int. Arch. Allergy Immunol. 105, 83-90 (1994). This model of pulmonary inflammation is IgE-mediated and involves eosinophilia (as in asthmatic humans). Bronchoalveolar lavage (BAL) fluid obtained from experimental animals can be evaluated for a number of parameters including soluble adhesion molecule expression and leukocyte accumulation. Adhesion molecule expression can be assessed by immunohistochemistry in experimental animal tissues, particularly in the lung. The action of the claimed compounds, such as MDL 29,353, should suppress the upregulation of VCAM-1 expression in BAL fluid and inhibit eosinophil accumulation. Inhibitors can be tested in a rat model of adjuvant arthritis that has previously been demonstrated to respond to anti-ICAM-1 monoclonal antibodies. Iigo Y. et al . , J. Immunol. 147, 4167-4171 (1991). In this model, adhesion molecule expression is evaluated in the limbs (joints) of experimental animals. For autoimmune diabetes, compounds can be tested for their ability to delay the onset of disease or block adoptive transfer of disease in a NOD mouse model. Heinke EW et al., Diabetes 42, 172-1730 (1993); Baron J. L et al., J. Clin. Inuest. 93, 1700-1708 (1994). In addition, the level of VCAM-1 expression in tissues (eg, pancreas) in laboratory animals can be monitored as well as the development of diabetes. The therapeutic potential for transplant rejection can be assessed by monitoring heart allograft survival (Balb / c heart transplanted into C3H / He recipients). Isobe M. et al . , J. Immunol. 153, 5810-5818 (1994). In vivo administration of anti-VCAM-1 and anti-VLA-4 monoclonal antibodies induces immunosuppression against cardiac allografts and soluble antigens in this mouse model. The effect of compounds on tumor metastasis and angiogenesis can be assessed in a number of models. These include the B16 (murine) and M24met (human) melanoma models for experimental metastasis. Fidler IJ, Cancer Res. 35, 218-224 (1975); Meuller BM et al., Cancer Res. 51, 2193-2198. The activity of the compound can be assessed by the effect of the compound on the number of lung metastases that develop as well as the compound effect on VCAM-1 expression in the lung as described above for the mouse respiratory model. A model for evaluating anti-angiogenic compounds that can be used to test compounds monitors vascular responses to a mixture of angiogenic factors mixed with basement membrane proteins injected subcutaneously into mice. Consists of. Passaniti A. et al . , Lab. Invest. 67, 519-528 (1992). Angiogenesis is assessed by the number of blood vessels increasing to matrigel and by the hemoglobin content of the gel. Adhesion molecule expression and leukocyte accumulation can be measured by immunohistochemical methods as in all the above examples.

Results The claimed compounds inhibit cytokine-induced upregulation of VCAM-1 gene expression in vascular cells in vitro. Selective inhibition of VCAM-1 expression compared to other cytokine-inducible adhesion molecule ICAM-1 was demonstrated against certain compounds of the claimed compounds (Table 3). In vivo experiments demonstrate that when fully accumulated, MDL 29,353 can inhibit LPS-induced levels of VCAM-1 expression in rabbit aortic endothelium (FIG. 1). This experiment also demonstrates that the compound has oral activity.

2 shows the effect of 2,6-di-tert-butyl-4-[(dimethylphenylsilyl) methylthio] phenol (MDL 29,353) on LPS-induced VCAM-1 expression in rabbit aorta in vivo. Data are expressed as% of aortic surface endothelial expressed VCAM-1 measured by immunostaining with anti-rabbit VCAM-1 antibody.

Claims (5)

formula

[Where,
R ₁ , R ₂ , R ₃ and R ₄ are each independently a C ₁ -C ₆ alkyl group;
Z is a thio, oxy or methylene group;
A is C ₁ -C ₄ alkylene group;
R ₅ is C ₁ -C ₆ alkyl or — (CH ₂ ) _n — (Ar) where n is an integer 0, 1, 2, or 3 and Ar is unsubstituted or is hydroxy, methoxy , Ethoxy, chlorine, fluorine or phenyl or naphthyl substituted by 1 to 3 substituents selected from the group consisting of C ₁ -C ₆ alkyl, provided that when Z is oxy, Ar is not phenyl or naphthyl substituted by only 1 to 3 substituents selected from the group consisting of hydroxy, methoxy, ethoxy, chlorine, or fluorine)]
An inhibitor of the expression of vascular cell adhesion molecule-1 induced by a cytokine containing the compound of Compound is
2,6-di-t-butyl-4-[(dimethylphenylsilyl) methylthio] phenol;
2,6-di-t-butyl-4-[(trimethylsilyl) methylthio] phenol;
2,6-di-t-butyl-4-[(dimethylphenylsilyl) methyloxy] phenol;
2,6-dimethyl-4-[(dimethylphenylsilyl) methyloxy] phenol;
2-t-butyl-6-methyl-4-[(dimethylphenylsilyl) methylthio] phenol;
2,6-di-tert-butyl-4-[(dimethyl-4-tert-butylphenylsilyl) methyloxy] phenol; or
The inhibitor according to claim 1, which is 2,6-di-t-butyl-4-[(benzyldimethylsilyl) methyloxy] phenol. formula

[Where,
R ₁ , R ₂ , R ₃ and R ₄ are each independently a C ₁ -C ₆ alkyl group;
Z is a thio, oxy or methylene group;
A is C ₁ -C ₄ alkylene group;
R ₅ is C ₁ -C ₆ alkyl or — (CH ₂ ) _n — (Ar) where n is an integer 0, 1, 2, or 3 and Ar is unsubstituted or is hydroxy, methoxy , Ethoxy, chlorine, fluorine or phenyl or naphthyl substituted by 1 to 3 substituents selected from the group consisting of C ₁ -C ₆ alkyl, provided that when Z is oxy, Ar is not phenyl or naphthyl substituted by only 1 to 3 substituents selected from the group consisting of hydroxy, methoxy, ethoxy, chlorine, or fluorine)]
A medicament for the treatment of chronic inflammatory diseases comprising the compound of Compound is
2,6-di-t-butyl-4-[(dimethylphenylsilyl) methylthio] phenol;
2,6-di-t-butyl-4-[(trimethylsilyl) methylthio] phenol;
2,6-di-t-butyl-4-[(dimethylphenylsilyl) methyloxy] phenol;
2,6-dimethyl-4-[(dimethylphenylsilyl) methyloxy] phenol;
2-t-butyl-6-methyl-4-[(dimethylphenylsilyl) methylthio] phenol;
2,6-di-tert-butyl-4-[(dimethyl-4-tert-butylphenylsilyl) methyloxy] phenol; or
The medicament according to claim 3, which is 2,6-di-t-butyl-4-[(benzyldimethylsilyl) methyloxy] phenol.   The medicament according to claim 3, wherein the inflammatory disease is asthma, chronic inflammation, rheumatoid arthritis, autoimmune diabetes, transplant tissue rejection or tumor angiogenesis.

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