CN1216921A - Method of inhibiting vascular cell adhesion molecule-1 and treating chronic inflammatory diseases with 2,6-di-alkyl-4-silyl-phenols - Google Patents
Method of inhibiting vascular cell adhesion molecule-1 and treating chronic inflammatory diseases with 2,6-di-alkyl-4-silyl-phenols Download PDFInfo
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Abstract
Disclosed is a methods useful for inhibiting VCAM-1 and for treating chronic inflammatory conditions in a patient in need thereof comprising administering to the patient effective amounts of a compound of formula (1) wherein R1, R2, R3 and R4 are each independently a C1-C6 alkyl group; Z is a thio, oxy or methylene group; A is a C1-C4 alkylene group; R5 is a C1-C6 alkyl or -(CH2)n-(Ar) wherein n is an integer 0, 1, 2 or 3; and Ar is phenyl or naphthyl unsubstituted or substituted with one to three substituents selected from the group consisting of hydroxy, methoxy, ethoxy, chloro, fluoro or C1-C6 alkyl.
Description
Background of invention
Vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) are the adhesion molecules in immunoglobulin superfamily, this family molecule in blood vessel and smooth muscle cell, be subjected to following cytokine to adjusted, for example, interleukin-1 (IL-1), interleukin 4 (IL-4) and tumor necrosis factor-
α(TNF-
α).By with the interaction of integrin counter receptor, the adhesion of VCAM-1 and ICAM-1 mediated leucocytes and stride the inwall migration in inflammatory reaction.VCAM-I and/or ICAM-1 inhibitor can be applicable to the chronic inflammatory disorder treatment of many types, comprise asthma, class pathogenic wind-warm arthritis and Autoimmune Diabetes.For example, the expression increase of asthma patient's VCAM-1 and ICAM-1 is well-known.Pilewski, J.M. etc., cellular elements biology is breathed by the U.S., and 12,1-3 (1995); Ohkawara, Y. etc., cellular elements biology is breathed by the U.S., and 12,4-12 (1995).In addition, the integrin receptor (being respectively VLA-4 and LFA-1) of blocking-up VCAM-1 and ICAM-1 can be suppressed at the early stage and late phase response in the abnormality respiratory response of an ovalbumin sensitization rat model simultaneously.Rabb, H.A. etc., U.S.'s respiratory care medical science, 149,1186-1191 (1994).
In addition, VCAM-1 is also relevant with other chronic inflammatory disorder as amboceptor, comprising as rheumatoid arthritis and Autoimmune Diabetes.For example, in rheumatoid arthritis people's blood capillary, find the increase that inwall adhesion molecule (comprising VCAM-1) is expressed.Koch, A.E. etc., experimentation 64,313-322 (1991); Morales-Ducret, J. etc., immunology 149,1421-1431 (1992).Anti-VCAM-1 or its counter receptor, the neutralizing antibody of VLA-4 can delay the outbreak of diabetes in the mouse model (NOD mice) of natural occurrence.Yang, X.D. etc., institute of NAS newspaper 90,10494-10498 (1993); Burkly, L.C. etc., diabetes 43,523-534 (1994); Raron, J.L. etc., Journal of Clinical Investigation 93,1700-1708 (1994).The monoclonal antibody of VCAM-1 is moved at animal model homology allogene also a kind of useful influence in the rejection of growing, this inhibitor that shows that VCAM-1 expresses can be useful in preventing transplant rejection.Orocz, C.G. etc., immunology communication 32,7-12 (1992).
VCAM-1 is expressed with film combination and soluble form by cell.The soluble form that has shown VCAM-1 can the intravital chemotaxis of induction of vascular endothelial cell, and stimulates the angiogenic effect in the rat cornea.Koch, A.E. etc., nature 376,517-519 (1995).The inhibitor that solubility VCAM-1 expresses has potential therapeutic value in the disease that treatment has than Johnson ﹠ Johnson's blood vessel component when (comprising tumor growth and transfer).Folkman, J. and Shing, Y., journal of biological chemistry 10931-10934 (1992).
Cloned and identified the promoter of VCAM-1 and ICAM-1.For example, two promoteres all contain multiple can be in conjunction with the DNA sequence element of transcription factor NF-kB.Iademarco, M.F. etc., journal of biological chemistry 267,16323-16329 (1992); Voraberger etc., Journal of Immunology 147,2777-2786 (1991).The NF-kB family of transcription factor plays a major role in the regulation and control of several genes of adjusted in to inflamed sites.As the activity of the NF-kB of transcription factor with relevant from dissociating of inhibition subunit IkB in kytoplasm.The NF-kB subunit is transferred to nuclear, with the specific DNA sequences combination of elements, and the transcribing of the some genes of reactivate (comprising VCAM-1 and ICAM-1).Collins T. etc., experimentation 68,499-508 (1993).
Supposed VCAM-1 expression of gene regulation and control can by specific to weaken-oxidation (oxidoreduction) responsive transcribe or transcribe after regulatory factor and with the oxidative stress coupling.Antioxidant pyrollidine dithiocar-bamate and N-acetylcystein can suppress the expression of inductive cytokine VCAM-1, but do not suppress the expression of ICAM-1 in vascular endothelial cell.Mauri, N. etc., Journal of Clinical Investigation 92,1866-1874 (1993).This shows and can suppress the expression of VCAM-1 by the antioxidant that comprises some additional factor and do not regulate the expression of ICAM-1.
Parker etc. (at United States Patent (USP) 5,155, on October 13rd, 250, one nine nine two issued) disclose 2, and 6-dialkyl group-4-silicyl-phenol can be used as antiatherosclerotic.In addition, disclose 2 in PCT international publication (WO95/15760, on June 15th, 1 published), 6-dialkyl group-4-silicyl-phenol can be used as serum cholesterol lowering agent.
The influence of the release of control VCAM-1 and treatment VCAM-1 mediation can be useful.Control or treatment VCAM-1 inflammation also can be useful and can not supervene side effect as known use anti-inflammatory steroid dose and the agent of anti-inflammatory on-steroidal.
Summary of the invention
Found now and the corresponding chemical compound of formula (1):
Wherein
R
1, R
2, R
3And R
4Group is respectively C separately
1-C
6Alkyl;
Z is a sulfur, oxygen or methylene;
A is C
1-C
4Alkylidene;
R
5Be C
1-C
6Alkyl or-(CH
2)
n-(Ar) group, wherein n represents integer 0,1, and 2 or 3; And Ar representative is not substituted the phenyl or naphthyl that base replaces, or the phenyl or naphthyl that is replaced by one to three group in the group in following group: hydroxyl, methoxyl group, ethyoxyl, chlorine, fluorine or C
1-C
6Alkyl, they can be used for suppressing cytokine-inductive VCAM-1 and express.This compounds can dose a patient with and suppress VCAM-1; Suppress or treat the influence of VCAM-1 mediation; And the inflammation of inhibition or treatment VCAM-1 mediation.This chemical compound can be used the influence under following situation that suppresses or treat the VCAM-1 mediation, as chronic inflammatory disease, and asthma, rheumatoid arthritis and Autoimmune Diabetes.
The accompanying drawing summary
Fig. 1 has illustrated 2,6-two-tert-butyl-4-[(xylyl silicyl) methyl mercapto] influence in phenol (MDL29,353) the body that the VCAM-1 in lipopolysaccharide-induced rabbit large artery trunks is expressed.The percent that data are expressed VCAM-1 by large artery trunks surface endothelium is represented, measures with the immunostaining of anti-rabbit VCAM-1 antibody.
Detailed Description Of The Invention
As employed at this paper, term " C1-C
6Alkyl " refer to the straight chain that forms to six carbon atom by, the saturated hydrocarbyl of side chain and cyclic configuration. The group that this term scope comprises has methyl, ethyl, just-and propyl group, isopropyl, just-and butyl, isobutyl group, sec-butyl, the tert-butyl group, just-amyl group, just-hexyl, cyclohexyl and analog thereof.
Similarly, term " C1-C
4Alkylidene " refer to the straight chain that forms to four carbon atom by, the saturated hydrocarbyl of side chain and cyclic configuration. The group that this term scope comprises has methylene, 1,2-ethane-two base, 1,1-ethane-two base, 1,3-propane-two base, 1,2-propane-two base, 1,3-butane-two base, Isosorbide-5-Nitrae-butane-two base and analog thereof.
At those R5Be-(CH2)
n-(Ar) in the situation of group, " (CH2)
n-" part represents the alkyl of a saturated linear configuration. Term " n " is defined as integer 0,1, and 2 or 3. Therefore, " (CH2)
n-" partly represent a key, methylene, 1,2-ethane, two base or 1,3-propane, two bases. And the representative of " (Ar) " part is by the defined aromatic radical of substituted or unsubstituted phenyl or naphthyl. Those-(Ar) group is in the situation of substituted aromatic radical, any position of its phenyl or naphthyl can be with 1 to 3 substituting group, unless its position is replaced by hydrogen atom. Substituting group is selected from following group: hydroxyl, methoxyl group, ethyoxyl, chlorine, fluorine and C1-C
6Alkyl. At term " (CH2)
n-(Ar) " specifically comprise phenyl in the scope; Naphthyl; Benzyl; Phenethyl; 3,4,5-trihydroxy phenyl; 3,4,5-trimethoxyphenyl; 3,4,5-triethoxy phenyl; The 4-chlorphenyl; The 4-aminomethyl phenyl; 3,5-di-tert-butyl-hydroxy phenyl; The 4-fluorophenyl; 4-chloro-1-naphthyl; 2-methyl isophthalic acid-menaphthyl; The 2-menaphthyl; 4-chlorobenzene methyl; The 4-tert-butyl-phenyl; 4-tert-butyl benzene methyl and analog thereof.
The compound of formula (1) can be by using the preparation of known method and technology, and be those of ordinary skills clearly. The general synthetic schemes of preparation formula (1) compound provides in option A, and wherein Z represents sulphur or oxygen; And unless otherwise indicated, all substituting groups all are that the front is defined.
Option A
2 3 1a
Z ＇=S or O
X=chlorine, bromine or iodine,
In general; the phenol of structure 1a can be by with suitable 2 of structure 2; 6-dialkyl group-4-mercapto-phenol or 2; 6-dialkyl group hydroquinone (or suitable derivant of taking protecting group) and non-nucleophilic base such as sodium hydride; potassium carbonate or cesium carbonate; and the suitable halo alkylidene silane of structure 3 (as suitable chloro alkylidene silane) reaction and preparing; this preparation feedback carries out in suitable aprotonic solvent; this solvent has acetonitrile; N; dinethylformamide or N,N-dimethylacetamide, or in aqueous solution such as water/2-butanone, carry out.
The initial substance that uses in the generalized general synthetic method in the option A is easier to obtain with regard to those of ordinary skill in the art.For example, and some phenol starting material of the multiple chemical compound of formula (1) (wherein Z is a sulfur, as 2, and 6-di-t-butyl-4-mercapto-phenol) in the U.S. the 3rd, 576, No. 883 patents, the 3rd, 952, No. 064 patent is all described among the 3rd, 479, No. 407 patents and the Japanese patent application 73-28425.Also have, the silicyl initial substance of the multiple chemical compound of formula (1) is as (trimethyl silyl)-methyl iodide, (trimethyl silyl) methyl bromide, (trimethyl silyl) chloromethane, (1-chloropropyl) trimethyl silane, then synthesizing 4, describing in 318-19 (1988) and the American Chemical Society's magazine 105,5665-75 (1983).Other method that is used to prepare suitable silane comprises Grignard reaction, for example 4-bromo methoxybenzene and magnesium metal react the formation Grignard reagent, and this reagent of reuse and chloro dimethyl chloride methyl-monosilane react and obtain chloromethyl dimethyl-4-anisyl silane.
In addition, methoxybenzene can by with the reaction lithiumation of Δ-butyl lithium, formed lithium compound reacts with the chloro dimethylsilane again, obtains chloromethyl dimethyl-2-anisyl silane.
In those examples; the 1-phenol functional group that is structure 2 chemical compounds can react with structure 3 chemical compounds under the specified conditions of this reaction, can be used in the 1-phenol functional group of well-known and general accepted standard phenol protective agent protection structure 2 chemical compounds in this area.Selecting and utilizing special blocking group is that those of ordinary skills know.In general, selected blocking group should be able to be protected mentioned phenol fully in follow-up synthesis step, and is easily removed under the condition that can not cause the purpose product degradation.
The example of suitable phenol protecting group is an ethers, as methoxy, and 2-methoxy ethoxy methyl, THP trtrahydropyranyl, tert-butyl and benzyl; Silyl ether is as trimethyl silyl and tert-butyl dimetylsilyl; Esters is as acetas and benzoate; Carbonate is as methylcarbonate and benzyl carbonate; And sulfonate, as metilsulfate and toluene fulfonate.
At those R wherein
1, R
2All be in the example of tert-butyl each other, the reaction of option A can be carried out easily and need not to protect its 1-phenol functional group.
The typical case of the following example representative described in option A is synthetic.These examples only are understood that with explaining, and are not intended to limit the scope of the invention by any way.As used herein, following term has clear and definite meaning: " g " refers to gram; " mmol " refers to mM; " mL " refers to milliliter; " bp " refers to boiling point; " ℃ " refer to degree centigrade; " mmHg " refers to millimetres of mercury; " mp " refers to fusing point; " mg " refers to milligram; " μ M " refers to the micromole; " μ g " refers to microgram.
Embodiment 1
2,6-two-tert-butyl-4-[(xylyl silicyl) methyl mercapto] phenol (MDL29,353)
Mix 2,6-two-tert-butyl-4-mercapto-phenol (2.4 grams, 10 mMs), potassium carbonate (1.4 grams, 10 mMs) and chloromethyl xylyl silane (1.9 grams, 10 mMs) and N, dinethylformamide (50 milliliters), and in argon, stir under the room temperature and spend the night.With ice-water dilution and with ether extracting mixture.Elder generation's water reuse salt water washing ether layer filters by flourosil-sodium sulfate, and then, evaporation becomes orange (3.5 gram).By the distillation purifying product first time (boiling point 160-170 She Shidu @0.1 millimetres of mercury), then, carry out silica gel chromatography (CCl
4: CHCl
3/ 1: 1) obtain title compound, a kind of lurid grease, its meeting crystallization at leisure forms a kind of white waxy solid (2.3 grams, 59%)
C
23H
34OSSi analyzes: value of calculation: C, 71.44; H, 8.86; S, 8.29;
Measured value: C, 71.14; H, 8.86; S, 7.98.
Embodiment 2
2,6-two-tert-butyl-4-[(trimethyl silyl) methyl mercapto] phenol (MDL28,235)
Mix 2,6-two-tert-butyl-4-mercapto-phenol (2.4 grams, 10 mMs), potassium carbonate (1.4 grams, 10 mMs), and N,N-dimethylacetamide (50 milliliters), and in argon, stir under the room temperature.Adding chloromethyl trimethyl silane (1.3 grams, 10 mMs) back stirs and spends the night.Heating is 2 hours on steam bath, cooling back dilute with water.The extracting of reuse ether, after the drying, evaporation becomes a kind of lurid solid (2.8 gram), last recrystallization (CH
3CN) obtain 1.1 the gram (34%) title compound, fusing point is 100-101 degree centigrade.
C
18H
32OSSi analyzes: value of calculation: C, 66.60; H, 9.88; S, 9.88;
Measured value: C, 66.83; H, 10.05; S:9.91.
Embodiment 3
2,6-dimethyl-4-[(trimethyl silyl) methoxyl group] phenol
Mix 2,6-dimethyl hydroquinone (1.4 grams, 10 mMs), potassium carbonate (1.4 grams, 10 mMs), chloromethyl trimethyl silane (1.9 grams, 10 mMs) and N, dinethylformamide (50 milliliters).In noble gas, stir up to reacting completely under the room temperature.With ice-water dilution and with ether extracting mixture.Elder generation's water reuse salt water washing ether layer filters by flourosil-sodium sulfate.Then, evaporation is to obtain title compound, reuse silica gel chromatogram purification.
Embodiment 4
2,6-two-tert-butyl-4-[(4-chlorophenyl dimetylsilyl) methoxyl group] phenol (MDL104,280)
Refluxed under nitrogen 2 in acetonitrile (200 milliliters), 6-two-tert-butyl benzo hydroquinone (13.7 grams, 61.6 mMs), potassium carbonate (9.4 grams, 68 mMs), the potassium iodide of chloromethyl (4-chlorphenyl) dimethylsilane (14.9 grams, 68 mMs) and catalytic amount is three days.Cross filter solid and evaporation.Be dissolved in the ethyl acetate again, and the water washing of water reuse salt, dry in anhydrous magnesium sulfate then, filter and evaporation.Remove low boiling impurity by being distilled to 135 ℃ @0.1 millimetress of mercury, then product of distillation (boiling point: the orange of purification gained ℃ @0.1 millimetres of mercury).Crystalline product can be from the hexane recrystallization to obtain tiny white needle (7.4 grams, 27% productive rate) through leaving standstill.Fusing point: 102-105 degree centigrade.
C
23H
33ClO
2Si analyzes: value of calculation: C, 68.20; H, 8.21
Measured value: C, 68.39; H, 8.13
NMR(CDCl
3):7.53(d,2H,J8.3),7.34(d,2H,J8.3)6.79(s,2H),4.73(s,1H),3.71(s,2H),1.42(s,18H),0.41(s,6H)。
Embodiment 5
2,6-two-tert-butyl-4-[(dimethyl-4-fluoro phenyl silicyl) methoxyl group] phenol (MDL104,389)
Refluxed under nitrogen 2 in acetonitrile (1500 milliliters), 6-two-tert-butyl benzo hydroquinone (10.0 grams, 45 mMs), potassium carbonate (6.2 grams, 45 mMs) and dimethyl (4-fluorophenyl) iodo-methyl silane (13.2 grams, 45 mMs) three days.Cross filter solid and evaporation.Be dissolved in the ethyl acetate again, and the water washing of water reuse salt, use anhydrous magnesium sulfate drying then, filtering and evaporating becomes very lurid grease, the crystallization through leaving standstill of this grease.This material can be from methanol recrystallization and obtain a kind of white crystalline solid (5.9 grams, 34% productive rate).Fusing point: 90-93 degree centigrade.
C
23H
33FOSi analyzes: value of calculation: C, 71.09; H, 8.86
Measured value: C, 70.96; H, 8.58
NMR(CDCl
3):7.58(dd,2H,J8.5,6.2),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)。
Embodiment 6
2,6-two-tert-butyl-4-[(xylyl silicyl) methoxyl group] phenol (MDL103,902)
Refluxed under nitrogen 2 in acetonitrile (125 milliliters), 6-two-tert-butyl benzo hydroquinone (5.43 grams, 24.4 mMs), potassium carbonate (3.7 grams, 26.8 mMs) and dimethyl (iodo-methyl) phenyl silane (7.4 grams, 26.8 mMs) spend the night.Cross filter solid and evaporation.Be dissolved in the ethyl acetate again, and the water washing of water reuse salt, use anhydrous magnesium sulfate drying then, filter and evaporation.Remove low boiling impurity by being distilled to 135 ℃ @0.1 millimetress of mercury, then product of distillation (boiling point: the orange of purification gained 155-165 ℃ @0.1 millimetres of mercury).Crystalline product can be from recrystallizing methanol to obtain white solid (5.8 grams, 64% productive rate) through leaving standstill.Fusing point: 82-83 degree centigrade.
C
23H
34O
2Si analyzes: value of calculation: C, 74.54; H, 9.25
Measured value: C, 74.51; 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)。
Embodiment 7
2,6-two-tert-butyl-4-[(dimethyl-4-methoxyphenyl silicyl) methoxyl group] phenol (MDL105,074)
Refluxed under nitrogen 2 in acetonitrile (200 milliliters), 6-two-tert-butyl benzo hydroquinone (13.7 grams, 61.1 mMs), potassium carbonate (9.4 grams, 68 mMs), the potassium iodide of chloromethyl (dimethyl)-4-anisyl silane (14.6 grams, 68 mMs) and catalytic amount is three days.Cross filter solid and evaporation.Be dissolved in the ethyl acetate again, and the water washing of first water reuse salt, use anhydrous magnesium sulfate drying then, filter and evaporation.Remove low boiling impurity by being distilled to 135 ℃ @0.1 millimetress of mercury, then product of distillation (boiling point: the orange of purification gained 155-165 ℃ @0.1 millimetres of mercury).Crystalline product can obtain a kind of white solid (4.9 grams, 19% productive rate) from the hexane recrystallization through leaving standstill.Fusing point: 122-123 degree centigrade.
C
24H
36O
3Si analyzes: value of calculation: C, 71.95; H, 9.06
Measured value: C, 71.80; H, 9.00
NMR(CDCl
3):7.53(d,2H,J8.6),6.93(d,2H,J8.6),6.80(s,2H),4.71(s,1H),3.81(s,3H),3.70(s,2H),1.42(s,18H),0.39(s,6H)。
Embodiment 8
2,6-dimethyl-4-[(xylyl silicyl) methoxyl group] phenol (MDL103,719)
In acetonitrile (150 milliliters), reflux 2 under the argon, 6-dimethyl hydroquinone (10.0 grams, 72.4 mMs), potassium carbonate (10.0 grams, 72.4 mMs), and dimethyl (chloromethyl) phenyl silane (13.4 grams, 72.4 mMs) 72 hours.After the thing cooling to be mixed, dilute with water is also used ether extraction.Gained grease distills under 145 to 160 She Shidu @0.1 millimetres of mercury conditions, obtains the lurid grease of 4.9 grams.
C
17H
22O
2Si analyzes: value of calculation: C, 71.28; H, 7.74
Measured value: C, 71.27; H, 7.74.
Embodiment 9
2-tert-butyl-6-methyl-4-[(xylyl silicyl) methyl mercapto] phenol (MDL104,518)
Backflow 2-tert-butyl-6-methyl-4-mercapto-phenol (11.8 grams, 60.1 mMs) under the argon in isopropyl alcohol (150 milliliters), potassium bicarbonate (6.0 grams, 11.8 mMs) and dimethyl (chloromethyl) phenyl silane (11.1 grams, 60.1 mMs) 24 hours.After the thing cooling to be mixed, dilute with water is also used ether extraction.The ether layer is evaporated to the grease that obtain 21.9 grams after doing.This grease distills the light yellow oil that obtains 5.5 grams under 145-160 degree centigrade of (0.1 millimetres of mercury) condition.
C
20H
28OSSi analyzes: value of calculation: C, 69.71; H, 8.19
Measured value: C, 69.76, H, 8.20.
Embodiment 10
2,6-two-tert-butyl-4-[(dimethyl-2-methoxyphenyl silicyl)-methoxyl group] phenol (MDL104,036)
Reflux chloromethyl dimethyl (2-methoxyl group) phenyl silane (27.2 grams, 0.127 mole), the mixture of sodium iodide (19 grams, 0.127 mole) and acetonitrile (350 milliliters) 28 hours.Cooling mixture is to ambient temperature and add 2,6-two-tert-butyl-1,4-hydroquinone (31.5 grams, 0.14 mole) and potassium carbonate (20.8 grams, 0.15 mole).The backflow mixture is 7 days in nitrogen.Cooling mixture, injection water (400 milliliters) is with ethyl acetate (400 milliliters) and separate organic layer.Evaporation organic layer and in silica gel (hexane/ethyl acetate: 9/1) go up the chromatography residue.Recrystallization (methanol) chromatography product obtains a kind of solid product (15.6 gram, 31%) of white.Fusing point: 89-90 degree centigrade.
C
24H
36O
3Si analyzes: value of calculation: C, 71.95; H, 9.06
Measured value: C, 71.84; H, 9.05.
Embodiment 11
2,6-two-tert-butyl-4-[(dimethyl-2,5-Dimethoxyphenyl silicyl)-methoxyl group] phenol (MDL103,016)
As prepare and use chloromethyl dimethyl-2 the chemical compound of front, 5-dimethoxy-phenyl silane (14 grams, 57 mMs) is prepared as silane, obtains a kind of white solid.Fusing point: 103-104 degree centigrade.
C
25H
38O
4Si analyzes: value of calculation: C, 69.72; H, 8.89
Measured value: C, 69.71; H, 8.72.
Embodiment 12
2,6-two-tert-butyl-4-[(dimethyl-2,3-Dimethoxyphenyl silicyl) methoxyl group] phenol (MDL108,750)
As above use chloromethyl (dimethyl)-2,3-dimethoxy-benzene base silane (11.3 grams, 46 mMs) is prepared as silane, obtains a kind of white solid.Fusing point: 94.5-96 degree centigrade.
C
25H
38O
4Si analyzes: value of calculation: C, 69.72; H, 8.89
Measured value: C, 69.84; H, 8.91.
Embodiment 13
2,6-two-tert-butyl-4-[(dimethyl-4-tert-butyl phenyl silicyl)-methoxyl group] phenol (MDL106,630)
As above use 4-tert-butyl phenyl chloromethyl-dimethylsilane (6.2 grams, 25.7 mMs) to be prepared, obtain a kind of white solid as silane.Fusing point: 114-115 degree centigrade.
C
27H
42O
2Si analyzes: value of calculation: C, 76.00; H, 9.92
Measured value: C, 75.94; H, 10.13.
Embodiment 14
2,6-two-tert-butyl-4-[(benzyl dimethyl silicyl) methoxyl group] phenol (MDL107,411)
As above use benzyl chloromethyl-dimethylsilane (7.13 grams, 35.9 mMs) to be prepared, obtain a kind of white solid as silane.Fusing point: 76-77 degree centigrade.
C
24H
36O
2Si analyzes: value of calculation: C, 74.95; H, 9.43
Measured value: C, 74.94; H, 9.36.
Embodiment 15
2,6-two-tert-butyl-4-[(dimethyl-right-methoxy-benzyl silicyl) methoxyl group] phenol (MDL108,816)
Step a; The preparation of dimethyl-right-methoxy-benzyl-chloromethyl silane: in nitrogen, in polytetrafluoroethylene agitator, stir magnesium and cut (9.7 grams, 0.4 gram atom) and spend the night.Activatory ＂ magnesium of this ＂ and adding iodine crystal suspend in dried THF (100 milliliters).THF (400 milliliters) solution that adds right-methoxyl group-benzyl bromide a-bromotoluene (80.8 grams, 0.4 mole) with certain speed is in suspension and make solution keep gentle backflow again.In case application of sample is finished, it is complete up to nearly all magnesium consumption to continue stirring (1-2 hour).Add THF (200 milliliters) solution of dimethyl chloride methylchlorosilanes (52.7 milliliters, 0.4 mole) with the dropping mode, and this mixture at room temperature stirred spend the night.With saturated aqueous ammonium chloride (500 milliliters) cancellation reactant mixture, immediately in stirring at room (～2 hours).The magnesium salt of filtering-depositing is also used ether (300 milliliters) dilution.Separate organic facies, water (3 * 250 milliliters) again, anhydrous magnesium sulfate drying is used in saturated sodium-chloride water solution (3 * 250 milliliters) washing then, filters and evaporation.Brown oil by the distillation purifying gained obtains title compound.Productive rate: 55%, boiling point: be 110-115 degree centigrade under 5 millimetress of mercury.
C
10H
15ClOSi analyzes: value of calculation: C, 55.93, H7.15.
Measured value: C, 55.40, H, 7.15.
Step b; 2,6-two-tert-butyl-4-[(dimethyl-right-methoxy-benzyl-silicyl) methoxyl group] phenol (MDL108,816) preparation: (28 grams of reflux dimethyl-right-methoxy-benzyl-chloromethyl silane in acetonitrile (250 milliliters), 0.13 mole), sodium iodide (0.5 gram, catalytic amount) and 2,6-two-tert-butyl benzyl hydroquinone (23 grams, 0.1 mole) and the mixture of cesium carbonate (32 gram, 0.1 mole) 6 days.The mixture of water and ethyl acetate (respectively getting 400 milliliters) is injected in the cooling back.Then separate organic layer, be dried, evaporation was also heated residue 3 hours with 110 degrees centigrade temperature (0.1mm) on the Kugelrohr device, with 140-160 degree centigrade temperature reheat 2 hours.Obtain waxy solid product (20.9 grams, 39%) through placing this residue of curing.Fusing point: 58-60 degree centigrade.
C
25H
38O
3Si analyzes: value of calculation: C, 72.41, H, 8.87.
Measured value: C, 70.29, H, 8.96.
Following compounds can prepare by the similarity method described in the foregoing description 1-14:
2,6-two-tert-butyl-4-[(triethylsilyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(diethyl phenyl silicyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(tripropyl silicyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(dipropyl phenyl silicyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(triisopropyl silicyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(diisopropyl phenyl silicyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(tributyl silicyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(dibutyl phenyl silicyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(tri-iso-butylsilyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(diisobutyl phenyl silicyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(three-tert-butyl silicyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(two-tert-butyl phenyl silicyl) methyl mercapto] phenol
2,6-two-methyl-4-[(trimethyl silyl) methyl mercapto] phenol
2,6-two-methyl-4-[(xylyl silicyl) methyl mercapto] phenol
2,6-two-methyl-4-[(dibutyl phenyl silicyl) methyl mercapto] phenol
2,6-two-methyl-4-[(three-tert-butyl silicyl) methyl mercapto] phenol
2,6-two-methyl-4-[(two-tert-butyl phenyl silicyl) methyl mercapto] phenol
2,6-two-ethyl-4-[(trimethyl silyl) methyl mercapto] phenol
2,6-two-ethyl-4-[(xylyl silicyl) methyl mercapto] phenol
2,6-two-ethyl-4-[(three-tert-butyl silicyl) methyl mercapto] phenol
2,6-two-ethyl-4-[(two-tert-butyl phenyl silicyl) methyl mercapto] phenol
2,6-two-propyl group-4-[(trimethyl silyl) methyl mercapto] phenol
2,6-two-propyl group-4-[(xylyl silicyl) methyl mercapto] phenol
2,6-two-isopropyl-4-[(trimethyl silyl) methyl mercapto] phenol
2,6-two-isopropyl-4-[(xylyl silicyl) methyl mercapto] phenol
2,6-two-butyl-4-[(trimethyl silyl) methyl mercapto] phenol
2,6-two-butyl-4-[(xylyl silicyl) methyl mercapto] phenol
2,6-dimethyl-4-[(trimethyl silyl) methoxyl group] phenol
2,6-dimethyl-4-[(xylyl silicyl) methoxyl group] phenol
2,6-dibutyl-4-[(triethylsilyl) methoxyl group] phenol
2,6-dibutyl-4-[(diethyl phenyl silicyl) methoxyl group] phenol
2,6-two-tert-butyl-4-[(trimethyl silyl) methoxyl group] phenol
2,6-two-tert-butyl-4-[(xylyl silicyl) methoxyl group] phenol.
The general synthetic schemes of preparation formula 1 chemical compound (wherein Z is a methylene) is listed in option b, and all substituent groups wherein all are to define in the past unless otherwise noted.
Option b
1b
In general, the phenol of structure 1b can prepare according to two step processes of option b.In step a, the halo alkylidene silane and the magnesium metal of suitable structure 3 react in suitable aprotonic solvent (as ether), thereby form magnesium halide.Magnesium halide (Grignard reagent) then and suitable structure 43,5-dialkyl group-4-hydroxyl-benzaldehyde (or derivant of suitable band protecting group) reacts and obtains the alcohol of structure 5.In step b, by a series of reduction techniques that are well known in the art and extensively adopt and method also the alcohol of original structure 5 obtain the phenol of required structure 1b.For example, the alcohol of structure 5 can adopt the Birch reduction to make it to be reduced with the sodium reaction in liquid ammonia.
The initial substance that the general building-up process of being summarized in option b adopts very easily obtains or can easily prepare according to standard technique and process.In order to prevent that unwanted side reaction from taking place, 3 of the structure 4 in option b, the 1-phenol functional group of 5-dialkyl group-4-hydroxyl-benzaldehyde can adopt the phenol protective agent of standard to be protected before Grignard reaction is carried out according to the front described in the option A.
The following examples representative is in typical the synthesizing described in the option b.These examples only are understood that with explaining, and are not intended to limit the scope of the invention by any way.
Embodiment 16
2,6-dimethyl-4-[2-(trimethyl silyl) ethyl] phenol
Step a: mixed magnesium is cut (240 milligrams, 10 mMs) and absolute ether in noble gas.The anhydrous ether solution that adds chloromethyl trimethyl silane (1.9 grams, 10 mMs).Stirring is dissolved up to magnesium metal.Add 3 again, the anhydrous ether solution of 5-dimethyl-4-hydroxy benzaldehyde (1.5 grams, 10 mMs).Stirring is up to reacting completely.Add saturated ammonium chloride solution after reactant mixture is cooled to 0 degree centigrade.Separate the ether layer, wash with water and dry (MgSO
4).Obtain 4-hydroxyl-3 after the evaporation, 5-dimethyl-α-[(trimethyl silyl)-methyl] benzyl alcohol then, uses the silica gel column chromatography purification.
Step b: mixed sodium metal (520 milligrams, 22.6 mMs) and liquid ammonia (13 milliliters).In the mode that drips, in this solution, add 4-hydroxyl-3, ethanol (0.5 gram) and ether (5 milliliters) solution of 5-dimethyl-α-[(trimethyl silyl)-methyl] phenyl methanol (2.22 grams, 10 mMs).After the blueness of solution disappears, add entry (13 milliliters) carefully, the extracting of reuse ether, dry (MgSO
4), and evaporating solvent.Obtain title compound by silica gel chromatography purification residue.
In addition, formula 1 chemical compound (wherein Z is a methylene) can be according to the method preparation of listing in scheme C, and all substituent groups wherein all are to define in the past unless otherwise noted.
Scheme C
In general, the phenol of preparation structure 1b can form magnesium halide by use the suitable monosilane elder generation and magnesium metal reaction of structure 3 in suitable aprotonic solvent such as ether.This magnesium halide (Grignard reagent) is suitable 3 with structure 6 then, and 5-dialkyl group-4-hydroxyl-benzyl halogenide (or derivant of suitable band protecting group) reacts and obtains the phenol of required structure 1b.
The initial substance that the general building-up process of being summarized in scheme C adopts very easily obtains or can easily prepare according to standard technique and process.For example, 3, the preparation of 5-dimethyl-4-acetoxyl group-benzyl bromide a-bromotoluene is at tetrahedron 33, and 3097-103 is described in (1977).Can be by the standard hydrolysis process with 3,5-dimethyl-4-acetoxyl group-benzyl bromide a-bromotoluene is transformed into corresponding phenol starting material.
In order to prevent that unwanted side reaction from taking place, 3 of the structure 6 in scheme C, the 5-dialkyl group-halid 1-phenol of 4-hydroxyl-benzyl functional group can adopt the phenol protective agent of standard to be protected before Grignard reaction is carried out according to the front described in the option A.
The following examples representative is in typical the synthesizing described in the scheme C.These examples only are understood that with explaining, and are not intended to limit the scope of the invention by any way.
Embodiment 17
2,6-diethyl-4-[2-(trimethyl silyl) ethyl] phenol
Mixed magnesium is cut (240 milligrams, 10 mMs) and absolute ether in noble gas.The anhydrous ether solution that adds chloromethyl trimethyl silane (1.9 grams, 10 mMs).Stirring is dissolved up to magnesium metal.Add 4-bromomethyl-2 again, the anhydrous ether solution of 6-diethyl phenol (2.43 grams, 10 mMs), and the backflow mixture is up to reacting completely.Pour the mixture and the stratum disjunctum of ice/hydrochloric acid into.Washing ether layer, dry (MgSO
4) and evaporation, obtain title compound (it is by the silica gel chromatography purification).
Following compounds can prepare by the similar process described in the above embodiments 16:
2,6-dipropyl-4-[2-(trimethyl silyl) ethyl] phenol
2,6-dipropyl-4-[2-(xylyl silicyl) ethyl] phenol
2,6-diisopropyl-4-[2-(trimethyl silyl) ethyl] phenol
2,6-diisopropyl-4-[2-(xylyl silicyl) ethyl] phenol
2,6-diisobutyl-4-[2-(trimethyl silyl) ethyl] phenol
2,6-diisobutyl-4-[2-(xylyl silicyl) ethyl] phenol
2,6-dibutyl-4-[2-(trimethyl silyl) ethyl] phenol
2,6-dibutyl-4-[2-(xylyl silicyl) ethyl] phenol
2,6-two-tert-butyl-4-[2-(trimethyl silyl) ethyl] phenol
2,6-two-tert-butyl-4-[2-(xylyl silicyl) ethyl] phenol
2,6-two-tert-butyl-4-[2-(three-tert-butyl silicyl) ethyl] phenol
2,6-two-tert-butyl-4-[2-(two-tert-butyl phenyl silicyl) ethyl] phenol
2,6-dimethyl-4-[2-(trimethyl silyl) ethyl] phenol
2,6-dimethyl-4-[2-(xylyl silicyl) ethyl] phenol.
The chemical compound that is appreciated that formula (1) can exist with various stereoisomeric forms in any ratio.All stereoisomeric forms in any ratio consistent with the said structure formula (standard convention according to expression stereoisomerism structure is explained) all are believed to comprise within the scope of the present invention.
The chemical compound of formula (1) (for example 2,6-two-alkyl-4-silicyl phenols) is well known in the art.Specifically, the chemical compound of formula (1) is at United States Patent (USP) 5,155, is described in 250.The chemical compound of preferred formula (1) is those its R
1And R
2Be C
4Alkyl, R
3And R
4Be C
1Alkyl, A are C
1Alkylidene, and R
5Be-(CH
2)
n-(Ar) group, wherein n represents 0 and the Ar representative is not substituted the phenyl that base replaces, or the phenyl that is replaced by one to three group in the group in following group: hydroxyl, methoxyl group, ethyoxyl, chlorine, fluorine or C
1-C
6Alkyl.More preferably chemical compound 2,6-two-tert-butyl-4-[(xylyl-silicyl) methyl]-sulfo--phenol.
As employed at this paper, term ＂ patient ＂ refers to the homoiothermic animal or the mammal of the diseases associated with inflammation of suffering from special VCAM-1 mediation.Can be understood as Cavia porcellus, Canis familiaris L., cat, rat, mice, hamster, rabbit and primates (comprising the people) they all are the examples of the patient within this term scope.
What term " chronic inflammation disease " referred to appraisable stimulus object of shortage or microbial pathogens is the disease or the situation of feature with persistent inflammation.Diseases associated with inflammation with formula (1) compounds for treating will be particularly useful in following disease, comprise: asthma, and chronic inflammatory disease, rheumatoid arthritis, Autoimmune Diabetes, transplant rejection and tumor vessel take place.Particularly preferred formula (1) chemical compound comprises when treating the patient's who needs this treatment diseases associated with inflammation:
2,6-two-tert-butyl-4-[(xylyl silicyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(trimethyl silyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(4-chlorophenyl dimetylsilyl) methoxyl group] phenol;
2,6-two-tert-butyl-4-[(dimethyl-4-fluoro phenyl silicyl) methoxyl group] phenol
2,6-two-tert-butyl-4-[(xylyl silicyl) methoxyl group] phenol
2,6-two-tert-butyl-4-[(dimethyl-4-methoxyphenyl silicyl) methoxyl group] phenol;
2,6-dimethyl-4-[(xylyl silicyl) methoxyl group] phenol
2-tert-butyl-6-methyl-4-[(xylyl silicyl) methyl mercapto] phenol
2,6-two-tert-butyl-4-[(dimethyl-2-methoxyphenyl silicyl)-methoxyl group] phenol
2,6-two-tert-butyl-4-[(dimethyl-2,5-Dimethoxyphenyl silicyl)-methoxyl group] phenol
2,6-two-tert-butyl-4-[(dimethyl-2,3-Dimethoxyphenyl silicyl)-methoxyl group] phenol
2,6-two-tert-butyl-4-[(dimethyl-4-tert-butyl phenyl silicyl)-methoxyl group] phenol
2,6-two-tert-butyl-4-[(benzyl dimethyl silicyl) methoxyl group] phenol.
After the ＂ of the chemical compound of formula (1) treatment effective dose ＂ is meant the patient used with single agent or multi-agent, can alleviate the amount of the symptom relevant with inflammation disease.After the effective vascular cell adhesion molecule-1 of the ＂ amount of suppression ＂ of the chemical compound of formula (1) refers to the patient used with single agent or multi-agent, can alleviate and amount by the relevant symptom of the disease of vascular cell adhesion molecule-1 mediation.As employed at this paper, inflammation disease or refer to the symptom performance by the alleviation ＂ of the ＂ symptom of the disease of vascular cell adhesion molecule-1 mediation and do not weaken when treating and be not to show the healing of disease or the complete obiteration of symptom than being expected at.The alleviation of symptom also comprises prevention.
When the effective dose of determining treatment or dosage, some factors need diagnostician to pay attention to, and include but not limited to: mammiferous species; Its size, age and general health status; Related concrete disease; The diseases range or the order of severity; The reaction of individual patient; Using of special compound; The mode of using; But the biology availability feature of the preparation of being used; The therapeutic scheme of selecting; The utilization of the medication of following; Also have other relevant situations simultaneously.
The treatment effective dose of the chemical compound of formula (1) generally by every day every kg body weight use one milligram (mg/kg/day) to every day every kg body weight use between five milligrams (mg/kg/day) and to change.Preferred dosage be every day from about 1 mg/kg to 500 mg/kg.Similarly, the amount of suppression of effective vascular cell adhesion molecule-1 of the chemical compound of formula (1) usually by every day every kg body weight use one milligram (mg/kg/day) to every day every kg body weight use between five milligrams (mg/kg/day) and to change.Preferred dosage be every day from about 1 mg/kg to 500 mg/kg.
Chemical compound of the present invention is the inhibitor that VCAM-1 expresses.We think that chemical compound of the present invention brings into play inhibitory action to VCAM-1 to adjusted by its cytokine, thereby prevention or amelioration of inflammation disease symptoms, these diseases comprise asthma, chronic inflammatory disease, rheumatoid arthritis, Autoimmune Diabetes and similar disease thereof.Yet, be appreciated that the present invention is not limited by any particular theory, be not used for explaining its usefulness in final utilization as known mechanism yet.
In the treatment to the patient, formula (1) chemical compound can comprise oral and parenteral approach so that chemical compound is used with any form or mode that effective dose obtains biological utilisation.For example, chemical compound can be oral, subcutaneous injection, intramuscular injection, intravenous injection, intradermal injection, intranasal, rectum and similar fashion administration.Oral way generally is preferred.Technical staff in the pharmaceutical field is according to the morbid state of required treatment, and the residing stage of disease, the situation relevant with other was easy to select appropriate method of application or form.The Remington pharmaceutical science, the 18th edition, Mack publishing company (1990).
Using formula (1) chemical compound can carry out with the form of pharmaceutical composition or medicine, these medicines are by making formula (1) chemical compound and acceptable pharmaceutical carrier or excipient composition, and its ratio and characteristic are determined by the medicinal practice of selected route of administration and standard.
Prepare this pharmaceutical composition or medicine in the mode that in pharmaceutical field, is widely known by the people.Its carrier or excipient can be solids, half-solid or liquid (it can be used as the carrier or the medium of active component).The carrier or the excipient that are fit to are well known in the art.This pharmaceutical composition goes for oral or parenteral uses, and with tablet, capsule, suppository, solution, the form of suspension or its analog is taken to the patient.
This pharmaceutical composition can be oral, and is for example, oral with inert diluent or edible carrier.Can be encapsulated in them in the gelatine capsule or be pressed into tablet.For reaching the purpose that oral medication is used, the chemical compound of formula (1) can be combined with excipient, and with tablet, lozenge, capsule, elixir, suspension, syrup, sugar-tablet, the form utilization of chewing solid gum and analog thereof.These preparations should comprise the chemical compound (active component) of 4% formula (1) at least, but it can change and can change between 4% and about 70% according to the per unit body weight easily according to particular form.The amount of the active component that exists in compositions is such, promptly can obtain to be fit to its unit dosage form of using.
This tablet, pill, capsule, lozenge and analog thereof also can contain in the following adjuvant one or more: binding agent, and as microcrystalline Cellulose, gum tragacanth or gelatin; Excipient is as starch or lactose; Disintegrating agent is such as alginic acid, Primogel, corn starch and analog; Lubricant is as magnesium stearate or Sterotex; The slippage agent is as silica sol; Sweeting agent, as adding sucrose or glucide, perhaps flavoring agent, as Herba Menthae, methyl salicylate or orange flavoring agent.As dosage unit form is capsule, and except that the material of the above-mentioned type, it can contain liquid-carrier such as Polyethylene Glycol or fatty oil.Other dosage unit form can contain other various materials (it can modify the physical form of unit dose), for example as coating materials.Like this, tablet or pill can be coated with last layer sugar, lac, perhaps other intestinal bag agent.Syrup can contain (except that active component) sucrose as sweeting agent and certain antiseptic, dyes and dyestuffs and flavorant.The material that is used to prepare these various compositionss should reach medicinal purity and non-toxicity on employed amount.
For reaching the purpose of parenteral administration, the chemical compound of formula (1) can mix in solution or the suspension.These preparations should contain at least 0.1% The compounds of this invention, but its incorporation can change between 0.1% to 50%.The amount of the active component that exists in said composition should be suitable.
Solution or suspension also should comprise one or more (the depending on the dissolubility of formula (1) chemical compound and other character) in the following adjuvant: sterile diluent such as water for injection, saline solution, fixing oil, Polyethylene Glycol, glycerol, propylene glycol or other synthetic; Antibacterial such as benzylalcohol or methyl butex; Antioxidant such as ascorbic acid or sodium sulfite; Chelating agen such as ethylenediaminetetraacetic acid; Buffer agent such as acetate, citrate or phosphate and reagent such as the sodium chloride or the glucose that are used for the toxicity adjusting.This parenteral administration can be encapsulated in ampoule, in disposable syringe or the multiple dose medicine bottle made by glass or plastics.
Embodiment 18
The cell surface enzyme-linked immunosorbent assay of VCAM-1 and ICAM-1
Contain in every hole on the 96 hole flat boards of 100 μ L culture medium with the density of every square centimeter 20,000 cell dull and stereotyped cultivate propagation human umbilical vein endothelial cell (HUVEC) or human aortic smooth muscle cell (HASMC) (Clonetics, Santiago, CA).(maintenance two days CA) is gone up in Santiago to this culture, adds cytokine or medicine then for EGM or SMGM2, Clonetics at growth medium.The cytokine chemical compound that adds deduct added before the analysis of adhesion molecule level in 20 to 24 hours.With the concentration of every milliliter of 500-1000 unit in culture, add tumor necrosis factor (Genzyme, Cambridge, MA).With the concentration of every milliliter of 100-200pg in culture, add interleukin 4 (GIBCO-BRL, Gaithersburg, MD).[substance is to add chemical compound in the cytokine of serial dilution on the flat board in 96 independent holes and carry out to the flat board that contains cell by shifting 100 μ L.Do not change the culture medium of culture before the adding effector].Remove culture medium, use Hanks buffered saline solution (HBSS) at room temperature to wash monolayer twice simultaneously.Add this primary antibody (from Upstate biotech company, LakePlacid, the anti-people VCAM-1 of NY or from lmmunotech company, Westbrook, the anti-H-ICAM-1 of ME) (HBSS of 1 μ g/ml adds 5% newborn calf serum in each hole, GIBCO-BRL, Gaithersburg is MD) and 37 degrees centigrade of incubations one hour.With HBSS washing hole twice, then in each hole, add 100 μ L combine horseradish peroxidase (BioRad, Hercules, 1/1000 mountain sheep anti-mouse igg CA) in HBSS and 5% newborn calf serum diluent and 37 degrees centigrade of incubations one hour.With HBSS washing hole three times, (BioRad, Hercules is CA) in each hole then to add 100 μ L tmb substrates.The 1N sulphuric acid that adds 50 μ L shows the end reaction of blue back.Absorbance is sentenced plate reader at 450nm and is measured.IC
50Value is determined by the absorption value curve that serial dilution chemical compound (being dissolved in the dimethyl sulfoxine) is obtained.
This IC
50Value is defined as drug level, and this concentration 50% ground suppresses the expression of the adhesion molecule of cytokine induction.The maximum that the adhesion molecule of foundation level deduction in the culture of cytokine induction that adhesion molecule is expressed from culture expressed is to determine inductive level.Typically induce the about 5-7 of VCAM-1 doubly.Typically induce the about 5-10 of ICAM-1 doubly.In quadruplicate inspection hole, detect every kind of drug concentrations.The single-point detected value of chemical compound when 50 μ M is according to definite IC
50Method measure, different is that data representation is without basal expression being carried out gauged inhibition level.(basic adhesion molecule is expressed the 10-20% that accounts for whole abduction delivering).
Table 1 has been summed up the ability [by utilization human aortic smooth muscle cell (HASMC)] of the inhibition VCAM-1 of all cpds of the present invention.In these experiments, measure before the cell surface VCAM-1 level, earlier cell and interleukin 4 and listed chemical compound were cultivated about 20 hours altogether.An independent experiment is represented on every hurdle.
Table 1
| Compound number (MDL numbering) | HSMC-1 (% suppresses 50 μ M) | HSMC-2 (% suppresses 50 μ M) | HSMC-3 (% suppresses 50 μ M) | VCAM-1 (on average) |
| 28,235 | ????7.8 | ????18.0 | ????42.0 | ????22.6 |
| ??29,353 | ????58.0 | ????60.0 | ????46.0 | ????54.7 |
| ?103,719 | ????49.0 | ????42.0 | ????45.5 | |
| ?103,902 | ????49.0 | ????60.0 | ????43.0 | ????50.7 |
| ?104,280 | ????54.7 | ????63.0 | ????44.0 | ????53.9 |
| ?104,518 | ????4.4 | ????47.0 | ????26.0 | ????25.8 |
| ?105,074 | ????28.3 | ????52.0 | ????47.0 | ????42.4 |
Table 2 has been summed up the selectivity inhibition VCAM-1 of all cpds of the present invention or has been suppressed the ability of VCAM-1 and ICAM-1 [by utilization propagation human umbilical vein endothelial cell (HUVEC)] simultaneously.In these experiments, measure before the cell surface adhesion molecule expresses, earlier with individual hour of cell and tumor necrosis factor-alpha and the illustrated about 20-24 of the common incubation of chemical compound.
Table 2
| Compound number (MDL numbering) | VCAM-1 (% suppresses 50 μ M) * | ICAM-1 (% suppresses 50 μ M) @ |
| ????28,235 | ????4.3 | ????(3.0) |
| ????29,353 | ????8.7 | ????6.0 |
| ????103,719 | ????17.0 | ????77.0 |
| ????103,902 | ????25.3 | ????39.0 |
| ????104,280 | ????27.3 | ????22.0 |
| ????104,518 | ????(1.0) | ????78.0 |
| ????105,074 | ????20.0 | ????(8.0) |
*: the meansigma methods that refers to three mensuration
@: refer to the meansigma methods that secondary is measured
Table 3 has been described the activity of selected compounds, and the VCAM-1 that has detected its eight parts of serial dilutions cytokine inductions in vascular endothelial cell and smooth muscle cell expresses.The deduction that the VCAM-1 on basis expresses also is used for IC
50The calculating of value.Detect the inhibitory action of every kind of chemical compound in the same manner to ICAM-1.In vascular smooth muscle cell, do not find any inhibitory action (nearly 100 μ M).In vascular endothelial cell, have only MDL 103,902 to show the inhibitory action of significantly ICAM-1 being expressed at 50 and 100 μ M, it can illustrate by the minimizing that microscopic examination adheres to the cell quantity on tissue culture surface.
Table 3
| Compound number (MDL numbering) | ?VCAM-1,HUVEC ?(IC 50,μM) | ?ICAM-1,HSMC ?(IC 50,μM) |
| ????29,353 ????103,902 ????105,074 | ????19 ????11 ????12 | ????10 ????5 ????40 |
Embodiment 19
MDL29 in the rabbit aorta, 353 couples of VCAM-1 suppress in the body of adjusted
Before attacking with lipopolysaccharide (LPS, every animal via ear vein is injected 40 μ g), with adding or deducting 0.4% MDL29,353 recipe is fed three weeks of New Zealand white rabbit earlier.Behind lps injection, from every animal, shift out aorta in 4 hours and in phosphate buffered saline (PBS), wash it simply.VCAM-1 is implemented immunohistochemistry, by its tissue and RB1/9 antibody (mouse-anti rabbit VCAM-1) are incubated overnight altogether at 4 degrees centigrade.With biotinylated mountain sheep anti mouse secondary antibodies (60 minutes, RT) detect bonded RB1/9.By add Succ-PEG-DSPE-alkali phosphatase conjugate (30 minutes, RT) finish the dyeing of VCAM-1, then and BT red (biotechnology, 10, RT) incubation.Obtain the image that dyeing is organized with image analysis system, measure the percentage ratio that immunoreactive aorta inner skin takes place the antibody that shows with anti-VCAM thus.
The activity in vivo of these chemical compounds also can be determined in estimating other inflammatory models relevant with improving the VCAM-1 level.This class model of respiratory disorder (as asthma) is ovalbumin-sensitization model.Kung, T.T. etc., Int.Arch.Allergy Immunol.105,83-90 (1994).This model of lung inflammation is that IgE mediates and is attended by eosinophilia's (asthmatic patient also has this symptom).Some parameters of bronchoalveolar lavage (BAL) stream that obtains by laboratory animal be can assess, expression of solubility adhesion molecule and leukocytic accumulation comprised.Determine that adhesion molecule is expressed and within animal tissue, (especially lungs) to be undertaken by immunohistochemical method.The effect of required compound (as MDL29,353) should be suppress that VCAM-1 expresses to adjusted, and stop the accumulation of eosinophilic granulocyte in BAL stream.Can detect this inhibitor in suffering from the rat model of rheumatoid arthritis, the former monoclonal antibody of its antagonism ICAM-1 that shown can be reacted.Iigo, Y. etc., Journal of Immunology 147,4167-4171 (1991).In this model, adhesion molecule is expressed and will be determined in the extremity (joint) of laboratory animal.For Autoimmune Diabetes, people can check the delayed onset of chemical compound or the ability of the adoptive transfer that wards off disease in the NOD mouse model.Heinke, E.W. etc., diabetes 42,1721-1730 (1993); Baron, J.L. etc., J.Clin.Invest.93,1700-1708 (1994).In addition, people can monitor expression and monitoring diabetes the development and change in laboratory animal of VCAM-1 in tissue (for example pancreas).Treatment potentiality by monitoring heart allograft thing survival (being transplanted to the Balb/c heart among the C3H/He recipient) assessment transplant rejection.Isobe, M. etc., Journal of Immunology 153,5810-5818 (1994).Use the immunosuppressant that to induce heart allograft thing and soluble antigen in the body of anti-VCAM-1 and anti-VLA-4 monoclonal antibody.Chemical compound can obtain estimating in some models to the effect of neoplasm metastasis and blood vessel generation.These models comprise B16 (Mus) and the melanomatous experiment metastasis model of M24met (people).Fidler, I.J., cancer research 35,218-224 (1975); Meuller, B.M. etc., cancer research 51,2193-2198.Can be by them to the effect of the quantity of generation lungs transfer and as the described effect that they are expressed VCAM-1 in the lung of mouse breathing model being assessed the activity of this chemical compound.The model that is used to estimate the anti-angiogenic chemical compound can be used for checking these chemical compounds, and it is relevant to the vascular reaction of the blended angiogenic factor mixture of basement membrane protein (hypodermic in mice) with monitoring.Passaniti, A. etc., experimentation 67,519-528 (1992).Blood vessel quantity among the available matrigel of adding to takes place and estimates with gelationus content of hemoglobin in blood vessel.Leukocytic adhesion molecule is expressed and is accumulated as determining with immunohistochemical method in all above-mentioned examples.
The result
Desired chemical compound is suppressed at the cytokine of the VCAM-1 gene expression in vivo in the vascular cell-inductive to adjusted.Compare with another kind of cytokine-inductive adhesion molecule (ICAM-1), the selectivity that VCAM-1 expresses suppresses to demonstrate (table 3) in some member of desired chemical compound.Experiment shows in the body, when enough accumulating, and MDL29,353 can suppress the expression (Fig. 1) of the inductive VCAM-1 of LPS in the rabbit aorta endothelium.This experiment shows that also this compounds has Orally active.
Claims (46)
1. method that in the patient, suppresses the cytokine-abduction delivering of vascular cell adhesion molecule-1, this inhibitory action of said needs of patients, this method comprise the chemical compound of said patient being used the following formula of effective vascular cell adhesion molecule-1 amount of suppression:
Wherein
R
1, R
2, R
3And R
4Group is respectively C separately
1-C
6Alkyl;
Z is a sulfur, oxygen or methylene;
A is C
1-C
4Alkylidene;
R
5Be C
1-C
6Alkyl or-(CH
2)
n-(Ar) group, wherein n represents integer 0,1, and 2 or 3; And Ar representative is not substituted the phenyl or naphthyl that base replaces, or the phenyl or naphthyl that is replaced by one to three group in the group in following group: hydroxyl, methoxyl group, ethyoxyl, chlorine, fluorine or C
1-C
6Alkyl.
2. according to the process of claim 1 wherein R
1And R
2It is the tert-butyl group.
3. according to the method for claim 2, R wherein
3And R
4It is methyl.
4. according to the method for claim 3, wherein A is a methylene.
5. according to the method for claim 4, wherein Z is a thio group.
6. according to the method for claim 4, wherein Z is an oxygen.
7. according to the process of claim 1 wherein that said chemical compound is 2,6-two-tert-butyl-4-[(xylyl silicyl) methyl mercapto] phenol.
8. according to the process of claim 1 wherein that said chemical compound is 2,6-two-tert-butyl-4-[(trimethyl silyl) methyl mercapto] phenol.
9. according to the process of claim 1 wherein that said chemical compound is 2,6-two-tert-butyl-4-[(4-chlorphenyl dimetylsilyl) methoxyl group] phenol.
10. according to the process of claim 1 wherein that said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-4-fluorophenyl silicyl) methoxyl group] phenol.
11. according to the process of claim 1 wherein that said chemical compound is 2,6-two-tert-butyl-4-[(xylyl silicyl)-methoxyl group] phenol.
12. according to the process of claim 1 wherein that said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-4-methoxyphenyl silicyl) methoxyl group] phenol.
13. according to the process of claim 1 wherein that said chemical compound is 2,6-dimethyl-4-[(xylyl silicyl)-methoxyl group] phenol.
14. according to the process of claim 1 wherein that said chemical compound is 2-tert-butyl-6-methyl-4-[(xylyl silicyl) methyl mercapto] phenol.
15. according to the process of claim 1 wherein that said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-2-methoxyphenyl silicyl) methoxyl group] phenol.
16. according to the process of claim 1 wherein that said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-2,5-Dimethoxyphenyl silicyl) methoxyl group] phenol.
17. according to the process of claim 1 wherein that said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-2,3-Dimethoxyphenyl silicyl) methoxyl group] phenol.
18. according to the process of claim 1 wherein that said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-4-tert-butyl phenyl silicyl) methoxyl group] phenol.
19. according to the process of claim 1 wherein that said chemical compound is 2,6-two-tert-butyl-4-[(benzyl dimethyl silicyl)-methoxyl group] phenol.
20. according to the process of claim 1 wherein that said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-right-methoxy-benzyl silicyl) methoxyl group] phenol.
21. a treatment suffers from the patient's of chronic inflammation disease method, this method comprises the chemical compound to the following formula of said patient's administering therapeutic effective dose:
Wherein
R
1, R
2, R
3And R
4Group is respectively C separately
1-C
6Alkyl;
Z is a sulfur, oxygen or methylene;
A is C
1-C
4Alkylidene;
R
5Be C
1-C
6Alkyl or-(CH
2)
n-(Ar) group, wherein n represents integer 0,1, and 2 or 3; And Ar representative is not substituted the phenyl or naphthyl that base replaces, or the phenyl or naphthyl that is replaced by one to three group in the group in following group: hydroxyl, methoxyl group, ethyoxyl, chlorine, fluorine or C
1-C
6Alkyl.
22. according to the method for claim 21, wherein R
1And R
2It is the tert-butyl group.
23. according to the method for claim 22, wherein R
3And R
4It is methyl.
24. according to the method for claim 23, wherein A is a methylene.
25. according to the method for claim 24, wherein Z is a thio group.
26. according to the method for claim 24, wherein Z is an oxygen.
27. according to the method for claim 21, wherein said chemical compound is 2,6-two-tert-butyl-4-[(xylyl silicyl) methyl mercapto] phenol.
28. according to the method for claim 21, wherein said chemical compound is 2,6-two-tert-butyl-4-[(trimethyl silyl) methyl mercapto] phenol.
29. according to the method for claim 21, wherein said chemical compound is 2,6-two-tert-butyl-4-[(4-chlorphenyl dimetylsilyl) methoxyl group] phenol.
30. according to the method for claim 21, wherein said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-4-fluorophenyl silicyl) methoxyl group] phenol.
31. according to the method for claim 21, wherein said chemical compound is 2,6-two-tert-butyl-4-[(xylyl silicyl)-methoxyl group] phenol.
32. according to the method for claim 21, wherein said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-4-methoxyphenyl silicyl) methoxyl group] phenol.
33. according to the method for claim 21, wherein said chemical compound is 2,6-dimethyl-4-[(xylyl silicyl)-methoxyl group] phenol.
34. according to the method for claim 21, wherein said chemical compound is 2-tert-butyl-6-methyl-4-[(xylyl silicyl) methyl mercapto] phenol.
35. according to the method for claim 21, wherein said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-2-methoxyphenyl silicyl) methoxyl group] phenol.
36. according to the method for claim 21, wherein said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-2,5-Dimethoxyphenyl silicyl) methoxyl group] phenol.
37. according to the method for claim 21, wherein said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-2,3-Dimethoxyphenyl silicyl) methoxyl group] phenol.
38. according to the method for claim 21, wherein said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-4-tert-butyl phenyl silicyl) methoxyl group] phenol.
39. according to the method for claim 21, wherein said chemical compound is 2,6-two-tert-butyl-4-[(benzyl dimethyl silicyl)-methoxyl group] phenol.
40. according to the method for claim 21, wherein said chemical compound is 2,6-two-tert-butyl-4-[(dimethyl-right-methoxy-benzyl silicyl) methoxyl group] phenol.
41. according to the method for claim 21, wherein said diseases associated with inflammation is asthma.
42. according to the method for claim 21, wherein said diseases associated with inflammation is a chronic inflammatory disease.
43. according to the method for claim 21, wherein said diseases associated with inflammation is a class pathogenic wind-warm arthritis.
44. according to the method for claim 21, wherein said diseases associated with inflammation is an Autoimmune Diabetes.
45. according to the method for claim 21, wherein said diseases associated with inflammation is a transplant rejection.
46. according to the method for claim 21, wherein said diseases associated with inflammation is a tumor-blood-vessel growth.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US64147496A | 1996-04-30 | 1996-04-30 | |
| US08/641,474 | 1996-04-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1216921A true CN1216921A (en) | 1999-05-19 |
Family
ID=24572554
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97194268A Pending CN1216921A (en) | 1996-04-30 | 1997-03-12 | Method of inhibiting vascular cell adhesion molecule-1 and treating chronic inflammatory diseases with 2,6-di-alkyl-4-silyl-phenols |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0910384A1 (en) |
| JP (2) | JP2000509070A (en) |
| KR (1) | KR20000065102A (en) |
| CN (1) | CN1216921A (en) |
| AR (1) | AR006891A1 (en) |
| AU (1) | AU2209097A (en) |
| BR (1) | BR9709189A (en) |
| CA (1) | CA2252869A1 (en) |
| IL (1) | IL126744A0 (en) |
| NO (1) | NO985040L (en) |
| WO (1) | WO1997040837A1 (en) |
| ZA (1) | ZA973571B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325478C (en) * | 2004-04-01 | 2007-07-11 | 复旦大学 | Nano structured organic photoelectric material, and preparation method |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6133467A (en) * | 1997-06-25 | 2000-10-17 | Hoechst Marion Roussel, Inc. | 2,6-di-t-butyl-4-[(dimethyl-4-methoxyphenylsilyl)-methyl-oxy]phenol and 2,6-di-t-butyl-4-[(dimethyl-2-methoxy-phenylsilyl)methyloxy]phenol |
| EP0996623A1 (en) * | 1997-06-25 | 2000-05-03 | Hoechst Marion Roussel, Inc. | 2,6-DI-t-BUTYL-4- (DIMETHYL-4-METHOXYPHENYLSILYL) -METHYLOXY]PHENOL AND 2,6-DI-t-BUTYL-4- (DIMETHYL-2-METHOXY-PHENYLSILYL) -METHYLOXY]PHENOL |
| US6632810B2 (en) | 2001-06-29 | 2003-10-14 | Kowa Co., Ltd. | Cyclic diamine compound with condensed-ring groups |
| US6509329B1 (en) | 2001-06-29 | 2003-01-21 | Kowa Co., Ltd. | Cyclic diamine compound with 6-membered ring groups |
| US6472386B1 (en) | 2001-06-29 | 2002-10-29 | Kowa Co., Ltd. | Cyclic diamine compound with 5-membered ring groups |
| US6432957B1 (en) | 2001-06-29 | 2002-08-13 | Kowa Co., Ltd. | Piperazine derivative |
| US6552188B2 (en) | 2001-06-29 | 2003-04-22 | Kowa Co., Ltd. | Unsymmetrical cyclic diamine compound |
| US6605620B1 (en) | 2001-08-30 | 2003-08-12 | Kowa Co., Ltd. | Cyclic amine compounds and pharmaceutical composition containing the same |
| US6867221B2 (en) | 2001-08-30 | 2005-03-15 | Kowa Co., Ltd. | Cyclic amine compounds and pharmaceutical composition containing the same |
| US6395753B1 (en) | 2001-08-30 | 2002-05-28 | Kowa Co., Ltd. | Cyclic amine compounds and pharmaceutical composition containing the same |
| AU2002363318B2 (en) * | 2001-10-25 | 2008-09-11 | Atherogenics, Inc. | Compounds and methods for treating transplant rejection |
| JP2007509054A (en) * | 2003-10-17 | 2007-04-12 | アミリン・ファーマシューティカルズ，インコーポレイテッド | Silylphenol promotes vascular health |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4670421A (en) * | 1982-07-12 | 1987-06-02 | American Cyanamid Company | Antiatherosclerotic silanes |
| US5155250A (en) * | 1990-07-05 | 1992-10-13 | Merrell Dow Pharmaceuticals Inc. | 2,6-di-alkyl-4-silyl-phenols as antiatheroscerotic agents |
| US5380747A (en) * | 1992-10-30 | 1995-01-10 | Emory University | Treatment for atherosclerosis and other cardiovascular and inflammatory diseases |
| US5608095A (en) * | 1996-04-30 | 1997-03-04 | Hoechst Marion Roussel, Inc. | Alkyl-4-silyl-phenols and esters thereof as antiatherosclerotic agents |
-
1997
- 1997-03-12 CN CN97194268A patent/CN1216921A/en active Pending
- 1997-03-12 JP JP9538865A patent/JP2000509070A/en not_active Ceased
- 1997-03-12 BR BR9709189A patent/BR9709189A/en not_active Application Discontinuation
- 1997-03-12 WO PCT/US1997/003928 patent/WO1997040837A1/en not_active Application Discontinuation
- 1997-03-12 EP EP97915044A patent/EP0910384A1/en not_active Withdrawn
- 1997-03-12 CA CA002252869A patent/CA2252869A1/en not_active Abandoned
- 1997-03-12 AU AU22090/97A patent/AU2209097A/en not_active Abandoned
- 1997-03-12 IL IL12674497A patent/IL126744A0/en unknown
- 1997-03-12 KR KR1019980708693A patent/KR20000065102A/en not_active Application Discontinuation
- 1997-04-24 ZA ZA9703571A patent/ZA973571B/en unknown
- 1997-04-29 AR ARP970101750A patent/AR006891A1/en unknown
-
1998
- 1998-10-29 NO NO985040A patent/NO985040L/en unknown
-
2007
- 2007-11-08 JP JP2007290260A patent/JP2008088183A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325478C (en) * | 2004-04-01 | 2007-07-11 | 复旦大学 | Nano structured organic photoelectric material, and preparation method |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2008088183A (en) | 2008-04-17 |
| CA2252869A1 (en) | 1997-11-06 |
| IL126744A0 (en) | 1999-08-17 |
| KR20000065102A (en) | 2000-11-06 |
| WO1997040837A1 (en) | 1997-11-06 |
| AR006891A1 (en) | 1999-09-29 |
| NO985040D0 (en) | 1998-10-29 |
| BR9709189A (en) | 1999-08-10 |
| AU2209097A (en) | 1997-11-19 |
| JP2000509070A (en) | 2000-07-18 |
| ZA973571B (en) | 1997-10-30 |
| EP0910384A1 (en) | 1999-04-28 |
| NO985040L (en) | 1998-10-29 |
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