CN108250105B - Acid sphingomyelinase inhibitor and application thereof in related diseases - Google Patents

Abstract

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to acid sphingomyelinase. The invention provides acidityThe specific structure of the sphingomyelinase inhibitor is shown in a formula I. The invention also provides a synthetic method shown in the formula I and application of the synthetic method in diseases related to apoptosis and inflammation, including Atherosclerosis (AS), diabetes, emphysema, pulmonary edema, pulmonary fibrosis, cystic fibrosis, non-alcoholic fatty liver, Alzheimer's Disease (AD), Multiple Sclerosis (MS), cerebral apoplexy and depression.

Description

Acid sphingomyelinase inhibitor and application thereof in related diseases

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of an acid sphingomyelinase inhibitor shown in a formula I and application of the acid sphingomyelinase inhibitor in apoptosis and inflammation related diseases.

Background

Sphingomyelinase (SMase) hydrolyzes Sphingomyelin (SM) in the prolymidosome to form ceramides and phosphorylcholine. It has mainly 3 manifestations: acid sphingomyelinase (aSMase), neutral sphingomyelinase (nSMase) and alkaline sphingomyelinase (Alk-SMase). Research has shown that the biological activity of acid sphingomyelinase accounts for 90% of the total activity of SMase, and is the fastest and most direct way for ceramide production in prolymphatics (division of biomedical nuclear medicine, 2005, 29(1), 44-47).

Ceramide is an important second messenger, and can play a role in signal transduction and participate in various cell functions, such as regulation of cell growth, proliferation and mutation, apoptosis, regulation of protein secretion, participation in immune process and inflammatory reaction (progression in Lipid Research, 2016, 61: 51-62). To date, it has been found that a variety of endogenous and exogenous factors including tumor necrosis factor-alpha (TNF- α), interleukin-beta (IL- β), interferon- γ, and the like, as well as oxidative stress, ionizing radiation, uv irradiation, heat shock, trauma, bacterial infections, and chemical agents, and the like, can activate aSMase, resulting in the production and aggregation of large amounts of ceramide.

The acid sphingomyelinase-ceramide pathway is involved in the processes of inflammation and Apoptosis in vivo, and its excessive activation leads to the increase and accumulation of ceramide, and is involved in the development of various related diseases (Progress in Lipid Research, 2016, 61: 51-62; Apoptosis, 2015, 20: 607-620). Diseases involved include Atherosclerosis (AS), diabetes, emphysema, pulmonary edema, pulmonary fibrosis and Cystic Fibrosis (CF), nonalcoholic fatty liver, Alzheimer's Disease (AD), Multiple Sclerosis (MS), depression, etc. (The FASEB Journal, 2008, 22: 3419-. Declin et al found that aSMase deficiency not only reduced lipid deposition but also delayed plaque formation, with 80% reduction in the area of foam cell plaques in early rats with acid sphingomyelinase gene knockout, and a significant 40-50% reduction in atherosclerotic plaque formation (arterioscher, thromb vasc, biol., 2008, 28: 1723-. The extracellular ASM promotes the accumulation of a large amount of lipoproteins on the surface of damaged cells, induces the endocytosis of macrophages, and finally leads to the formation of foam cells. These pathological features are key factors in the development of atherosclerosis (Circulation, 2007, 116: 1832-1844; progression in Pharmaceutical Sciences, 2013, 37 (8): 383-389). activation of aSMase is also closely associated with ischemia reperfusion injury of the heart and brain. The inhibition of the activity of aMASe in an ischemia-reperfusion model can obviously inhibit apoptosis caused by ischemia-reperfusion injury and improve cardiac insufficiency or cerebral apoplexy (FEBS J., 2009, 276: 5579-5588). In addition, respiratory inflammation and repeated bacterial infections are the most prominent pathogenic features in CF patients, and aSMase and ceramide are important factors in the induction of these pathological processes. Clinical studies have demonstrated that restoration of normal levels of ceramide by functional inhibition of aSMase can significantly improve lung function and prolong survival in CF patients (Cell physiology. biochem., 2016, 39: 565-.

By inhibiting aSMase, the normal level of ceramide is restored, and the symptoms of related diseases can be effectively relieved. However, only substrate analogs, diphosphates, 3, 5-diphosphinositols and a few natural product classes have been reported as direct inhibitors of aSMase. And the reported molecules have the defects of poor selectivity, poor stability to phosphatase, poor membrane permeability and the like, and cannot be applied to the drug development of related diseases (Cell physiol.biochem.2010, 26: 01-08).

The research shows that the acid sphingomyelinase is a potential therapeutic target, the aMASe inhibitor has great therapeutic potential in inflammation-related diseases and apoptosis-related diseases, and the development of novel inhibitors for developing candidate drugs for treating the related diseases is urgently needed.

Disclosure of Invention

The invention provides a compound serving as a novel direct acid sphingomyelinase inhibitor, a preparation method and application thereof in medicines.

The acid sphingomyelinase inhibitor provided by the invention is a compound shown in a formula I.

X represents O, S, CH₂、NR₄、R₄Selected from H, C₁-C₃Straight chain alkyl group of (1), C₁-C₃Branched alkyl and C₃-C₆A cycloalkyl group of (a).

n is 0, 1, 2, or 3.

R₁Represents an alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group.

R₁Alkyl represented by C₅-C₁₄Straight chain alkyl group of (1), C₅-C₁₄Branched alkyl of C₃-C₇One of cycloalkyl groups of (a); r₁Aryl groups represented are phenyl, biphenyl, naphthyl; said aryl radical optionally bearing substituents R₅(ii) a The substituent R₅Is mono-or di-substituted and represents H, F, Cl, Br, I, NO₂、NH₂、CF₃、CN、C₁-C₈Straight chain alkyl group of (1), C₃-C₈Branched alkyl of C₃-C₆Cycloalkyl of, OR₆、NHR₆Or one of heterocyclic groups; wherein said R₆Selected from H, C₁-C₄OfChain alkyl radical, C₁-C₄Branched alkyl or C₃-C₆A cycloalkyl group of (a).

The term heterocyclic group as used herein refers to saturated heterocyclic groups and aromatic heterocyclic groups containing optionally one or more hetero atoms selected from oxygen, nitrogen and sulfur atoms.

R₂And R₃The same or different represent H, F, Cl, Br, CN and CH respectively and independently₃、CF₃、OCH₃、OCF₃、OCH₂CH₃、SCH₃、SCH₂CH₃、NHCH₃、NHCH₂CH₃、N(CH₃)₂、N(CH₂CH₃)₂And C₂-C₄Straight chain alkane of (1), C₂-C₄Branched alkane of (C)₃-C₆Is one of the cycloalkanes of (1).

The term alkane as used herein includes both saturated alkanes and unsaturated alkanes.

Another object of the present invention is to provide a process for the preparation of a compound of formula I:

the synthesis of the compound of formula I is as follows:

Y＝Cl，Br，I，OTf or OTs；R₈＝CH₃，CH₂CH₃，CH(CH₃)₂，C(CH₃)₃or Bn

under the conditions of alkali and catalyst, the initial raw material 1 or 2 and halogenated hydrocarbon are subjected to substitution reaction or Heck reaction with olefin to obtain an intermediate 3; wherein the alkali used in the substitution reaction is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, the dosage is 1-3 equivalents, the used catalyst is selected from one of potassium iodide and sodium iodide, the dosage is 0.01-0.1 equivalents, the solvent is acetone, and the temperature is reflux temperature; the catalyst used in the Heck reaction is one selected from palladium acetate, palladium ditriphenylphosphine chloride, palladium chloride and tetrariphenylphosphine palladium, the dosage is 0.01-0.1 equivalent, the used alkali is one selected from potassium carbonate, sodium carbonate, tripotassium phosphate, cesium carbonate, triethylamine and pyridine, the dosage is 1-3 equivalents, the solvent is one selected from toluene, xylene, N-dimethylformamide and 1, 2-dichloroethane, and the temperature is the reflux temperature of the used solvent.

Hydrolysis of compound 3 under basic conditions gives 4. Wherein the alkali is selected from potassium hydroxide, sodium hydroxide, and lithium hydroxide, the dosage is 3-10 equivalent, the solvent is water and methanol (volume ratio is 1: 1), and the temperature is 50-100 deg.C.

The intermediate 4 reacts with an acylating reagent to give compound 5. Wherein the acylating reagent is selected from one of thionyl chloride and oxalyl chloride, the dosage is 1-5 equivalents, the solvent is selected from one of dichloromethane, chloroform and tetrahydrofuran, and the temperature is the reflux temperature of the solvent.

The intermediate 5 is reacted with hydroxylamine and a base at room temperature to give the compound of formula I. Wherein the alkali is selected from one of sodium hydroxide, potassium carbonate, sodium carbonate and lithium hydroxide, the dosage is 4-6 equivalents, the solvent is selected from one of dichloromethane, chloroform and tetrahydrofuran, and the temperature is room temperature.

The invention also provides the application of the acid sphingomyelinase inhibitor in medicines.

Still another object of the present invention is to provide the use of the above-mentioned acid sphingomyelinase inhibitor or a pharmaceutically acceptable salt, ester or prodrug thereof for the manufacture of a medicament for the treatment of diseases associated with apoptosis and inflammation, including Atherosclerosis (AS), diabetes, emphysema, pulmonary edema, pulmonary fibrosis, cystic fibrosis, non-alcoholic fatty liver, Alzheimer's Disease (AD), Multiple Sclerosis (MS), stroke, depression.

Detailed Description

The present invention will be further illustrated by the following examples, but the present invention is not limited to the following examples.

EXAMPLE 1 part of the Synthesis of Compounds of the invention, including Ia-Ie and IIa-IIf, exemplified by Compound Ia

Preparation of 4-methoxy-3-octyloxybenzoic acid:

methyl 3-hydroxy-4-methoxybenzoate (1 g, 5.49mmol) was dissolved in 20mL of acetone, and potassium carbonate (2.27 g, 16.4mmol), potassium iodide (91 mg, 0.549mmol), and octyl bromide (1.27 g, 6.59mmol) were added thereto, and the mixture was heated to reflux for 10 hours and cooled to room temperature. The reaction solution was filtered, the filter cake was washed 3 times with dichloromethane, the organic phases were combined, the solvent was spin-dried to give a white solid, the obtained white solid was dissolved in 10mL of methanol, 10mL of water and 2.20g (54.9mmol) of sodium hydroxide were added, refluxing was carried out for 1h, cooling was carried out to room temperature, 15% aqueous HCl solution was added to adjust to acidity, and the product, 4-methoxy-3-octyloxybenzoic acid, was precipitated as a white solid, 1.43g, with a yield of 94.2%.¹H-NMR(300MHz，CDCl₃)，δ：0.90(t，3H，-CH₃)；1.28-1.46(m，10H，-(CH₂)₅-)；1.82-1.92(m，2H，-CH₂-)；3.96(s，3H，-OCH₃)；4.091(t，2H，-CH₂OAr)；6.93(m，1H，Ar-H)；7.25(m，2H，Ar-H)；ESI-MS(m/z)：295[M+H]⁺.

Preparation of 4-methoxy-3-octyloxy-N-hydroxy-benzamide (Ia):

1g (3.57mmol) of 4-methoxy-3-octyloxybenzoic acid was dissolved in 30ml of anhydrous dichloromethane, 1.28g (10.7mmol) of thionyl chloride and 1 drop of N, N-dimethylformamide were added, the mixture was heated to reflux for 1 hour, then cooled to room temperature, the solvent was dried by spinning, dissolved in anhydrous tetrahydrofuran, and added dropwise to a tetrahydrofuran solution containing 0.43g (10.7mmol) of NaOH and 0.74g (10.7mmol) of hydroxylamine hydrochloride. After the dropwise addition, the mixture is stirred for 5min at room temperature, and the crude product is dried by spinning, and the yield is 60 percent, wherein the crude product is 0.63g of column chromatography purified white solid N-hydroxy-4-methoxy-3-octyloxy benzamide. M.P.168-171 deg.c,¹H-NMR(300MHz，DMSO-d₆)：δ11.06(s，1H)，8.89(s，1H)，7.38-7.34(m，，2H)，7.01-6.98(m，1H)，3.99-3.95(t，J＝6.60Hz，2H)，3.79(s，3H)，1.74-1.67(m，2H)，1.41-1.39(m，2H)，1.27(m，8H)，0.87-0.84(m，3H)；¹³C NMR(75MHz，DMSO-d₆)：δ164.41，151.85，148.12，125.37，120.49，111.81，111.71，68.72，56.08，31.70，29.17，29.15，29.13，25.97，22.54，14.41；HRMS(ESI-TOF)：calcd for C₁₆H₂₆NO₄[M+H]⁺296.1856，found 296.1860.

3-decyloxy-N-hydroxybenzamide (Ib)

Referring to the synthesis of Ia, the product was a white solid with a yield of 77.8%. M.P.107-108 deg.C, 1H-NMR (300MHz, DMSO-d)₆)，δ：11.16(s，1H)，9.01(s，1H)，7.38-7.29(m，3H)，7.07-7.03(m，1H).4.01-3.96(t，J＝6.30Hz，2H)，1.74-1.69(m，2H)，1.41-1.37(m，2H)，1.25(m，12H)，0.88-0.83(t，J＝6.30Hz，3H)；¹³C NMR(75MHz，DMSO-d₆)：δ164.34，159.03，134.57，129.93，119.42，117.85，113.01，68.04，31.75，29.47，29.41，29.22，29.15，29.09，25.95，22.54，14.38；HRMS(ESI-TOF)：calcd for C₁₇H₂₈NO₃[M+H]⁺294.2064，found 294.2067.

3-Dodecyloxy-N-hydroxybenzamide (Ic)

Referring to the synthesis of Ia, the product was a white solid with a yield of 72.4%. M.P.115-117 deg.C,¹H-NMR(300MHz，DMSO-d₆)：δ11.18(s，1H)，9.02(s，1H)，7.36-7.29(m，2H)，7.06-7.04(m，1H)，4.00-3.96(t，J＝6.60Hz，2H)，1.73-1.69(m，2H)，1.41(m，2H)，1.24(m，16H)，0.85-0.83(m，3H)；¹³C NMR(75MHz，DMSO-d₆)：δ164.34，159.03，134.57，129.93，119.42，117.85，112.99，68.03，31.76，29.48，29.24，29.18，29.10，25.96，22.56，14.39；HRMS(ESI-TOF)：calcd for C₁₉H₃₂NO₃[M+H]⁺322.2377，found 322.2384.

3-Octyloxy-N-hydroxybenzamide (Id)

Referring to the synthesis of Ia, the product was a white solid with a yield of 68.9%. M.P.85-87 deg.C, 1H-NMR (300MHz, DMSO-d)₆)，δ：11.18(s，1H)，，9.01(s，1H)，7.34-7.29(m，3H)，7.06-7.04(m，1H)，4.01-3.96(t，J＝6.3Hz，2H)，1.74-1.69(m，2H)，1.41(m，2H)，1.26(m，8H)，0.86-0.38(m，3H)；¹³C NMR(75MHz，DMSO-d₆)：δ164.37，159.03，134.58，129.94，119.43，117.86，113.02，68.05，31.69，29.19，29.12，29.09，25.96，22.54，14.48；HRMS(ESI-TOF)：calcd for C₁₅H₂₄NO₃[M+H]⁺266.1751，found266.1747.

4-methoxy-3-dodecyloxy-N-hydroxybenzamide (Ie)

Referring to the synthesis of Ia, the product was a white solid with a yield of 74.7%. M.P.128-129 deg.C, 1H-NMR (300MHz, DMSO-d)₆)，δ：11.05(s，1H)，8.88(s，1H)，7.36(m，2H)，7.00(m，1H)，3.97(m，2H)，3.80(s，3H)，1.72(m，2H)，1.25(m，18H)，0.86(m，3H)；¹³C NMR(75MHz，DMSO-d₆)：δ164.04，151.88，148.15，125.39，111.88，111.74，68.74，56.08，31.76，29.48，29.17，25.97，22.54，14.37；HRMS(ESI-TOF)：calcd for C₂₀H₃₄NO₄[M+H]⁺352.2482，found 352.2482

3-benzyloxy-N-hydroxybenzamide (IIa)

Referring to the synthesis of Ia, the product was a white solid with a yield of 65.7%. M.P.174-176 ℃ and 1H-NMR (300MHz, DMSO-d)₆)，δ：11.22(s，1H)，9.06(s，1H)，7.48-7.31(m，8H)，7.18-7.14(m，1H)，5.15(s，2H)；¹³C NMR(75MHz，DMSO-d₆)：δ164.33，158.71，137.32，134.66，130.03，128.92，128.35，128.15，119.77，118.19，113.55，69.81；HRMS(ESI-TOF)：calcd for C₁₄H₁₄NO₃[M+H]⁺244.0968，found244.0969.

3- (4-bromobenzyl) -oxy-N-hydroxybenzamide (IIb)

Referring to the synthesis of Ia, the product was a light red solid in 72.3% yield, M.P.160-161 deg.C, 1H-NMR (300MHz, DMSO-d)₆)，δ：11.18(s，1H)，9.00(s，1H)，7.62-7.59(m，2H)，7.44-7.35(m，4H)，7.16-7.14(m，1H)，5.14(s，2H)；¹³C NMR(75MHz，DMSO-d₆)：164.26，158.51，136.80，134.66，131.85，130.24，121.46，119.88，118.19，113.58，68.99；HRMS(ESI-TOF)：calcd for C₁₅H₁₆NO₄[M+Na]⁺343.9897，found 343.9893.

3- ((4-nitrile) benzyl) -oxy-N-hydroxybenzamide (IIc)

Referring to the synthesis of Ia, the product was a white solid with a yield of 70.8%. M.P.160-162 deg.C, 1H-NMR (300MHz, DMSO-d)₆)，δ：11.21(s，1H)，9.05(s，1H)，7.89-7.86(m，2H)，7.67-7.64(m，2H)，7.41-7.37(m，3H)，7.19-7.15(m，1H)，5.27(s，2H)；¹³C NMR(75MHz，DMSO-d₆)：164.21，158.36，143.16，134.73，132.90，130.12，128.51，120.04，119.20，118.21，113.58，111.00，68.85；HRMS(ESI-TOF)：calcd for C₁₅H₁₃N₂O₃[M+H]⁺269.0921，found 269.0923.

3- ((4-methoxy) benzyl) -oxy-N-hydroxybenzamide (IId)

Referring to the synthesis of Ia, the product was a white solid with a yield of 70.0%. M.P.170-172 deg.C, 1H-NMR (300MHz, DMSO-d)₆)，δ：11.20(s，1H)，9.04(s，1H)，7.40-7.34(m，5H)，7.16-7.13(m，1H)，6.97-6.94(m，2H)，5.06(s，2H)，3.76(s，3H)；¹³C NMR(75MHz，DMSO-d₆)：164.34，159.50，158.76，134.61，129.97，129.16，119.19，118.19，114.30，113.55，69.60，55.55；HRMS(ESI-TOF)：calcd for C₁₅H₁₆NO₄[M+H]⁺274.1074，found 274.1076.

3-benzyloxy-4-methoxy-N-hydroxy-benzamide (IIe)

Referring to the synthesis of Ia, the product was a white solid with a yield of 81.3%. M.P.178-179 deg.C, 1H-NMR (300MHz, DMSO-d)₆)，δ：11.06(s，1H)，8.90(s，1H)，7.47-7.34(m，7H)，7.34-7.02(m，1H)，5.12(s，2H)，3.82(s，3H)；¹³C NMR(75MHz，DMSO-d₆)：δ164.37，152.03，147.79，137.39，128.87，128.34，128.26，125.39，120.88，112.59，111.85，70.48，56.16；HRMS(ESI-TOF)：calcd for C₁₇H₁₆NO₄[M+H]⁺274.1074，found 274.1079.

3- (4-bromobenzyl) -oxy-4-methoxy-N-hydroxybenzamide (IIf)

Referring to the synthesis of Ia, the product was a white solid with a yield of 85.8%. M.P.149-151 deg.C, 1H-NMR (300MHz, DMSO-d)₆)，δ：11.06(s，1H)，8.99(s，1H)，7.62-7.42(m，5H)，7.05-7.03(m，1H)，5.11(m，2H)，3.82(s，3H)；¹³C NMR(75MHz，DMSO-d₆)：164.26，151.99，147.55，136.88，131.82，130.31，125.36，121.46，120.99，112.63，111.85，69.65，56.17；HRMS(ESI-TOF)：calcd for C₁₅H₁₆NO₄[M+H]⁺352.0185，found 352.0179.

Example 2 Compounds Ia-Ig, IIa-IIf inhibit acid sphingomyelinase Activity.

The acid sphingomyelinase can hydrolyze sphingomyelin in cells to generate ceramide, different enzyme activities catalyze different amounts of products aiming at a certain amount of fluorescently-labeled reaction substrates, and the level of the enzyme activities can be inspected by detecting the content of the products. The invention carries out experimental design according to the principle. Extracting protein from cultured cells, adding buffer solution and fluorescently-labeled reaction substrate, adding compounds Ia-Ie and IIa-IIf with different concentrations, setting blank control group, performing fluorescence analysis after reaction, and calculating IC of the compounds₅₀The value is obtained.

The specific results are shown in the table:

table: acid sphingomyelinase inhibitory Activity of some of the Compounds of the invention

Claims (6)

1. An acid sphingomyelinase inhibitor having the structure represented by formula I:

in formula I:

x represents O;

n is 0;

R₁represents an alkyl group; r₁Alkyl represented by C₅-C₁₄Straight chain alkyl or C₅-C₁₄A branched alkyl group of (a);

R₂represents OCH₃；

R₃Represents H.

2. A pharmaceutical composition of a compound represented by formula I or a pharmaceutically acceptable salt thereof;

in formula I:

x represents O;

n is 0;

R₁represents an alkyl group; r₁Alkyl represented by C₅-C₁₄Straight chain alkyl or C₅-C₁₄A branched alkyl group of (a);

R₂represents OCH₃；

R₃Represents H.

3. The use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an acid sphingomyelinase inhibitor;

in formula I:

x represents O;

n is 0;

R₁represents alkyl, substituted or unsubstituted aryl;

R₂and R₃The same or different represent H, F, Cl and CH respectively and independently₃、CF₃、OCH₃、OCH₂CH₃、NHCH₃、NHCH₂CH₃、N(CH₃)₂、C₂-C₄Linear alkane of (2) and C₂-C₄One of the branched alkanes of (a);

R₁alkyl represented by C₅-C₁₄Straight chain alkyl or C₅-C₁₄A branched alkyl group of (a);

R₁aryl groups represented are phenyl, biphenyl, naphthyl; said aryl radical optionally bearing substituents R₅(ii) a The substituent R₅Is mono-or di-substituted and represents H, F, Cl, Br, I, NO₂、NH₂、CF₃、CN、C₁-C₈Straight chain alkyl group of (1), C₃-C₈Branched alkyl OR OR of₆One of (1); wherein said R₆Selected from H, C₁-C₄Straight chain alkyl or C₁-C₄Branched alkyl groups of (a).

4. Use according to claim 3, characterized in that R₁The aryl group represented means a phenyl group substituted at the para-position with a substituent hydrogen, fluorine, chlorine, bromine or iodine.

5. Use of a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of apoptosis and inflammation related diseases, said apoptosis and inflammation related diseases being atherosclerosis, diabetes, emphysema, pulmonary edema, pulmonary fibrosis, cystic fibrosis, non-alcoholic fatty liver disease, alzheimer's disease, multiple sclerosis, stroke, depression;

in formula I:

x represents O;

n is 0;

R₁represents an alkaneA substituted or unsubstituted aryl group;

R₂and R₃The same or different represent H, F, Cl and CH respectively and independently₃、CF₃、OCH₃、OCH₂CH₃、NHCH₃、NHCH₂CH₃、N(CH₃)₂、C₂-C₄Linear alkane of (2) and C₂-C₄One of the branched alkanes of (a);

R₁alkyl represented by C₅-C₁₄Straight chain alkyl or C₅-C₁₄A branched alkyl group of (a);

R₁aryl groups represented are phenyl, biphenyl, naphthyl; said aryl radical optionally bearing substituents R₅(ii) a The substituent R₅Is mono-or di-substituted and represents H, F, Cl, Br, I, NO₂、NH₂、CF₃、CN、C₁-C₈Straight chain alkyl group of (1), C₃-C₈Branched alkyl OR OR of₆One of (1); wherein said R₆Selected from H, C₁-C₄Straight chain alkyl or C₁-C₄Branched alkyl groups of (a).

6. Use according to claim 5, characterized in that R₁The aryl group represented means a phenyl group substituted at the para-position with a substituent hydrogen, fluorine, chlorine, bromine or iodine.