CN1260215C - Antagon of endostadin receptor pyrazole carboxylic acids - Google Patents

Abstract

The present invention relates to a compound of a general formula (I) and salts thereof, wherein R1, R2, and R3 are organic substituent groups. The compound of the present invention has the antagonistic activity of endothelin receptor, and can be used for treating cardio-cerebrovascular diseases, tumours, diabetes, kidney diseases, asthma, etc.

Description

Pyrazole carboxylic acid class endothelin-receptor antagonists

Technical field

The present invention relates to novel pyrazole carboxylic acid class endothelin-receptor antagonists and they are in treatment cardiovascular and cerebrovascular diseases, tumour, diabetes, the application in ephrosis, the asthma.

Background technology

The mortality ratio of cardiovascular and cerebrovascular diseases occupies first of all kinds of diseases, and its final cause of the death overwhelming majority is myocardial hypertrophy, heart failure (heart failure), cerebral apoplexy and lethality irregular pulse.Especially in recent years the case fatality rate of serious heart failure is high, has formed a difficult problem of international the world of medicine.These diseases all lack effective medicine at present.

Endothelin (ET) is known the strongest one of blood vessel factor that contracts of finding in 1988, and ETs comprises ET-1, ET-2 and ET-3.Mammals mainly contains two kinds of ET acceptor: ET _AAnd ET _BThe ET-1 that mainly is expressed in vessel wall and smooth muscle cell is ET optionally _AAcceptor has mediated contract blood vessel function and the short cell mitogen effect of ET-1; ET _BAcceptor is nonselective to ET-1, ET-2 and ET-3, is expressed in the ET of endotheliocyte _BReceptor-mediated nitrogen protoxide (NO) and prostacyclin I ₂(PGI ₂) release cause vasorelaxation.And be expressed in smooth muscle cell, mediate ET _BVasoconstriction behind the receptor activation.

The ET wide participation hypertension, myocardial ischemia, myocardial hypertrophy, congestive heart failure, renal failure, the pathologic process of the multiple diseases such as cerebral vasospasm that asthma and subarachnoid hemorrhage cause, blocking-up generation of endothelin or antagonism its with the combining of acceptor, can be used for the treatment of above-mentioned disease.The film of striding of the permeability of vascular endothelial cell and cell moves, and is subjected to the regulation and control of endothelin.So endothelin can influence tumour cell blood vessel endothelium passed through the new life of blood vessel and hemato encephalic barrier.Research is thought, endothelin-receptor antagonists will become and is used for the treatment of hypertension clinically, heart failure, subarachnoid hemorrhage, tumour, diabetes, the newtype drug of diseases such as ephrosis and renal failure, asthma, especially be used for treating chronic congestive heart failure, reverse myocardial hypertrophy, control hypertension and prevention of brain palsy.

Summary of the invention

The object of the present invention is to provide the new pyrazole carboxylic acid class endothelin-receptor antagonists of a class.

Application in the medicine of diseases such as the compound that another object of the present invention is to provide general formula (I) is in preparation treatment cardiovascular and cerebrovascular diseases, tumour, diabetes, and ephrosis, asthma, Tiroidina are hyperfunction.

Purpose of the present invention can reach by following measure:

On the basis of endothelin-receptor antagonists current research, the simulation in the drug application design, bioisostere, ultimate principles such as structure amalgamation, the compound of tool general formula (I) has been synthesized in design, and has carried out their bioactivity research.Wherein, especially meaningfully Compound I 13 (code name 0213), I14 (code name 0214).

Wherein, R ₁Be C ₁-C ₆Alkyl and thiazolinyl have one to four carbon atom carboxylic acid and ester class thereof at interval, have one to four carbon atom aryl and substituted aryl at interval, have one to four carbon atom heterocycle at interval; R ₂, R ₃Be H or halogen independently of one another.

R wherein ₁Can be C ₁-C ₄Alkyl, R ₂, R ₃Can be 4-chlorine independently of one another.

R wherein ₁Can be normal-butyl, R ₂, R ₃Can be 4-chlorine (code name 0213) independently of one another.

R wherein ₁Can be one to two carbon atom carboxylic acid and ester class thereof at interval, R ₂, R ₃Can be 4-chlorine.

R wherein ₁Can be carboxymethyl, R ₂, R ₃Can be 4-chlorine (code name 0214) independently of one another.

The general formula that the present invention comprises (I) compound can be made into various pharmaceutical dosage forms and pharmaceutical carrier.

The compound of general formula of the present invention (I) is used for preparing the application of the medicine for the treatment of cardiovascular and cerebrovascular diseases, pulmonary hypertension, heart failure, tumour, diabetes, ephrosis, asthma as endothelin-receptor antagonists.

The compound of general formula (I) can be synthetic by table 1 or table 2 method:

Table 1 reagent and condition: i, ArCH ₂Cl, K ₂CO ₃/ acetone; Ii, Ar ' CH ₂Cl, K ₂CO ₃/ DMF; Iii, (CO ₂Et) ₂, NaOEt/EtOH refluxes; Iv, 85%NH ₂NH ₂H ₂O/HOAc refluxes; V, R ₁X, K ₂CO ₃/ acetone, cocurrent flow; Vi, NaOH/EtOH/H ₂O, 10%HCl.

a：R ₁＝CH ₃ b：R ₁＝4-ClC ₆H ₄CH ₂

Table 2 reagent and condition: i, PhNHNH ₂, HOAc refluxes; Ii, 85%NH ₂NH ₂H ₂O/HOAc refluxes; Iii, CH ₃I or 4-ClC ₆H ₄CH ₂Cl, K ₂CO ₃/ acetone refluxes;

2,4 two substituted benzyl oxygen benzoylformaldoximes (3) generate compound (4) with the oxalic acid diethyl ester condensation, generate compound (5) with the hydrazine hydrate cyclization again.But (7) then can generate two kinds of isomerss (8) and (9) with the direct condensation of phenylhydrazine.Similarly isomers appears in the alkylated reaction to compound (5), for example for the hydrocarbylation of compound (10), use active high, the CH that steric hindrance is little ₃I makes alkylating reagent, generate almost the isomer of equivalent (11a) with (12a), and use the little of specific activity, steric hindrance is made hydrocarbylation reagent than big right-chlorobenzyl chloride in the reaction process, the selectivity of reaction obviously improves, and the product above 90% is isomer (11b).As seen, in the N-hydrocarbyl reaction of compound (5), steric effect plays an important role, and it has caused the primary product of this substitution reaction is A type structure.Part this type of isomer A that institute's separation and purification obtains or the constitutional features and the physicochemical constant of Type B compound are as follows:

With

Compound	R 1	R 2	R 3	A or B	Yield (%)	Mp.(℃)
							11a	CH 3	H	4-Cl	A	46	139-140
12a	CH 3	H	4-Cl	B	41	98-99
							11b	4-ClC 6H 4CH 2	H	4-Cl	A	89	124-126
12b	4-ClC 6H 4CH 2	H	4-Cl	B	9.6	117-118
							8	Ph	4-Cl	4-Cl	A	3.4	121-122
9	Ph	4-Cl	4-Cl	B	39	137-138

The physicochemical constant of general formula (I) representative compounds is as follows:

^aYield is meant the product yield that separation and purification is arrived

The finished product can be through column chromatographic isolation and purification or organic solvent recrystallizing and refining.

Prepare pharmaceutical dosage form with the included compound of the present invention as activeconstituents and only need use the conventional medicine preparation technique.Better with tablet and capsule.

The very strong endothelin receptor antagonizing activity of compound tool of the present invention is used for the treatment of cardiovascular disorder and tumour patient.Dosage range is about 0.1-10mg/kg/ day.

The endothelin receptor of representative compounds of the present invention is as follows in conjunction with experimental result:

Tab 1 compound is to the IC of ET-1 in conjunction with experiment ₅₀

Compound	IC 50(nM)
		I 01 I 02 I 03 I 04 I 05 I 06 I 07 I 08 I 09 I 10 I 11 I 12 I 13 I 14 I 15 I 16 I 17 I 18 I 19 I 20 I 21 I 22 I 23 I 24 I 25 I 26 I 27	2800 3000 1200 500 1000 1000 800 15 61 ＞1000 ＞1000 800 18 16 ＞1000 ＞1000 ＞1000 ＞1000 ＞1000 ＞1000 89 95 ＞1000 500 ＞1000 ＞1000 ＞1000

0213 the activity and the U.S. are close at the Bosentan of FDA approval in November calendar year 2001.Bosentan antagonism ET _AThe IC of R ₅₀Be 4.7nM, ET _BR is 95nM.0213 antagonism ET _AThe activity of R is doubled in Bosentan approximately, antagonism ET _BThe activity of R, two medicines are identical.Bosentan is to ET _AR/ET _BThe selectivity of R is 20.2.0213 compound is to ET _AR/ET _BThe selectivity of R is 36.2, is better than Bosentan.

0213 compound antagonism ET _AR and ET _BThe activity of R, the compound activity of developing with external many famous drugmakers is close.

The antagonism ET of table 0213 _AR and ET _BThe IC of the activity of R and external drugmaker new compound ₅₀Relatively

Compound	ET AR	ET BR	Selectivity
				0213 Bosentan SB217242 A182086 BQ123 TBC11251	2.57 4.7 1.1 94 37 1.4	93 95 100 1.3 - -	36.2 20.2 90.9 72.3 is single-minded

1. the ET of 0213 pair of blood vessel of endothelin-receptor antagonists _AAnd to bronchial ET _BThe activity intensity of acceptor

1.1 antagonism endothelin-1 (being called for short ET-1 or ET) is to vasoactive research, ET is very strong to the thoracic aorta contraction activity of endothelium-denuded.77 compounds all carry out antagonism ET and shrink active research quantitative examination, obtain 9 strong endothelin-receptor antagonists of compound activity such as 0213 grade, and wherein 0213 effect is the strongest.

1.2 shrinking the ET acceptor of endothelium-denuded rat chest aorta is ET _A, by S6 _CThe rat aorta ring contraction activity that causes endothelium-denuded is by ET _BWhat acceptor mediated.The result: 0213 compound is tied anti-ET _AThe PA of acceptor ₂Be 8.52 ± 0.26 (X ± SD, down together).Antagonism S6 _CCause ET _BThe PA of receptor-mediated bronchoconstriction ₂Be 6.56 ± 0.20.Antagonism ET _AIntensity be ET _B91.2 times.

2. endothelin-receptor antagonists 0213 radioreceptor activity analysis, the intensity of antagonism ET and studying ET respectively _AWith ET _BActivity intensity.

With ¹²⁵I-ET-1 competition receptor-ligand is in conjunction with test.Carrying out ET _ADuring the R selectively acting, add ET _BR agonist S6 _CSaturated to ET _BThe combination of R.Carry out ET _BDuring the R selectivity, add ET _ASelective exclusion agent PD156707 is with ET _AThe saturated combination of R.Obtain respectively: 0213 couple of ET _AThe IC of R ₅₀For 2.57_ ± 1.41nM (n=9), to ET _BThe IC of R ₅₀Be 93 ± 34nM (n=5), the activity of the two differs 36 times.Prompting: the 0213rd, ET _AR and ET _BThe dual antagonist of R, antagonism ET _AR is main.

3. the acute heart failure that causes of endothelin-receptor antagonists 0213 experimental therapy ligation rat coronary artery

0213 compound (100mg/kg, po.), behind 1 administration 1h of rat, open breast knot and prick arteria coroaria sinistra by urethane 1.2g/kg anesthesia.Survey haemodynamics: left chamber contractile function: LV+dp/dtmax, LVSP; And left chamber diastolic function: LV-dp/dtmin, LVDP.Observe 120min.

After 0213 administration, acute heart failure is to LVSP, and the reduction of LV-dp/dtmin and LV+dp/dtmax all improves significantly.The participation mechanism of ET is less in the acute heart failure, but still has obvious drug effect, and decreased heart rate is also had (as Fig. 1,2,3).

4. endothelin-receptor antagonists 0213 chronic administration obstructs the experimental therapy of chronic congestive heart failure rat afterwards to the heart

Behind the rat ligation arteria coroaria sinistra, form the model of the chronic congestive heart failure of 10d-70d.0213 sets up 30mg/kg/d and 100mg/kg/d po to give 60 days.Administration behind the coronary ligation the 11st day is carried out pharmacological agent after heart failure is formed again.Captopril 20mg/kg/d, 60 days.Rat behind coronary ligation 10 days and 70 days is got blood respectively and surveys ANP (atrial natriuretic peptide), more left chamber, right ventricle back and the body weight haemodynamics when of weighing.Two groups of pathological model groups are to ANP and RV/BW, and the comparison of LV/BW, the change of 10 and 70 days model group are compared with sham operated rats all very marked difference.Between 10 days and 70 days, LV+dp/dtmax, LVSP, LVDP, diastolic function, contractile function also have significant difference, but haemodynamics LV-dp/dtmin and LVDP, and mean arterial blood pressure (MPA) and HR do not see significant difference.At the tissue slice of pathological model, in 10 days models of infarct, matter has massive inflammatory cells infiltrated between cardiac muscle, and inflammatory cell infiltration obviously reduces in 70 days models.Because ANP showed increased and myocardial remodelling are more obvious in the 70d group, prompting is in the heart failure model of 70d, and body fluid mechanism fully starts, and keeping of myocardial remodelling and heart failure is relevant with humoral factor in the pathomechanism.

4.1 medicine 0213 and captopril treatment chronic congestion heart failure rat is to disappearing of the myocardial remodelling of congestive heart failure.

Ratio value representation with myocardium weight and the body weight of decline heart: left chamber/body weight (LV/BW), right ventricle/body weight (RV/BW), whole-heartedly/body weight (LW/BW).Medicine 0213 is at 30mg/kg and 100mg/kg, and po obviously alleviates left chamber myocardial hypertrophy, drug effect and captopril 20mg/kg, and po is similar.Compare with sham operated rats: the myocardium weight that chronic heart failure was organized (CHF10 days) in 10 days obviously increases, and the prompting myocardial remodelling is obvious, ^bP＜0.05, ^cP＜0.01.Myocardial remodelling in CHF70 days groups is more obvious.Compare with the SO group, ^cP＜0.01.With comparison in CHF10 days, myocardial remodelling more increased the weight of, ^fP＜0.01.0213 group obviously disappears myocardial remodelling, and with comparison in CHF70 days, two dosage groups all made and disappear, ^hP＜0.05, or ⁱP＜0.01.Participating in medicine is that captopril is also effective.(as Fig. 4)

4..2 hemodynamic curative effect to congestive heart failure.

The contractile function LV+dp/dtmax of chronic failure heart obviously descends, and diastolic function is also obviously depleted, and the rising of LV-dp/dtmin and LVDP is all very remarkable.Medicine 0213 and Captopril group are to the haemodynamics LV+dp/dtmax of failure heart, and LV-dp/dtmin and LVDP all obviously improve (seeing Fig. 5,6,7).

4..3 medicine 0213 improves the increasing of blood plasma ET.ANP concentration of congestive heart failure.Medicine 0213 dosage 30 and 100mg/kg, the po treatment is compared with the heart failure rat of infarct after 70 days, obviously reduces ET in the blood plasma, the concentration of ANP.(see figure 8).

4.4 pharmacological agent is to the change of the mRNA expression of prepro-ET-1 and ANP in the chronic heart failure rat pathology cardiac muscle.The prepro-ET-1mRNA of the myocardium of left ventricle of chronic heart failure rat expresses obviously and descends, and the mRNA of ANP obviously rises.(seeing Fig. 9,10)

MRNA in the cardiac muscle of chronic heart failure rat expresses showed increased.In myocardial infarction 10 days and 70 days groups, obviously more than sham operated rats (SO).Compare with sham operated rats (SO): ^aP＞0.05, ^bP＜0.05, ^cP＜0.01.Medicine 0213 100mg/Kg group is expressed obviously mRNA and is reduced.With infarct 10 days relatively: ^dP＞0.05, ^eP＜0.05, ^fP＜0.01; With infarct 70 days relatively: ^gP＞0.05, ^hP＜0.05, ⁱP＜0.01.

The mRNA of Prepro-ET-1 expresses, increases with sham operated rats is apparent in view in 10 days groups of infarct, ^cP＜0.01,70 a day group also increases, ^bP＜0.05.0213100mg/Kg group po makes the mRNA of Prepro-ET-1 express obviously downward modulation.Compare with sham operated rats (SO): ^aP＞0.05, ^bP＜0.05, ^cP＜0.01.With infarct 10 days relatively: ^dP＞0.05, ^eP＜0.05, ^fP＜0.01; With infarct 70 days relatively: ^gP＞0.05, ^hP＜0.05, ⁱP＜0.01.

Brief summary prompting endothelin antagonist 0213 can be used for treating acute, chronic heart failure, and curative effect is good.

5. the therapeutic action of 0213 pair of pulmonary hypertension of medicine is obvious.Obviously improve the RVSP (being equivalent to the pulmonary artery blood pressure) of pulmonary hypertension rat and the RV myocardium reconstruct of disappearing, reduce index such as ET-1 and prepro-ET-1 in the blood plasma.

6. 0213 pair of thyroxine of medicine causes the improvement of myocardosis and cardiovascular pathological changes.

Cause myocardiac cardiovascular function unusual by the multidose Levothyroxinnatrium, medicine 0213 tool improves significantly.

1. medicine 0213 Levothyroxinnatrium that disappears causes 30.6% (p＜0.01) of myocardial remodelling.

2. reduce ET-1 concentration 43.6% (p＜0.01) in the blood plasma of cardiomyopathy model.

3. gene Kv1.4 in the pathology cardiac muscle, Kv4.2, and the mRNA of Kv4.3 downward modulation is significantly, is transferred to normal in medicine 0213 treatment obviously.

4. medicine 0213 makes obviously improvement of myocardosis damage under the myocardiac Electronic Speculum.

5. the iNOS activity increases in the Tiroidina disposition myocardosis, and medicine 0213 makes and reduces by 82.5% (p＜0.01).ENOS is active in this myocardosis descends, and medicine 0213 makes the active raising 87.2% of eNOS, (p＜0.01).

6. cNOS extremely obviously reduces in the Tiroidina disposition myocardosis, and medicine 0213 makes 100% to raise, and returns to normally (p＜0.01) fully.The mRNA of iNOS obviously raises in myocardosis, and medicine 0213 raises the expression 100% of iNOSmRNA, and p＜0.01 is recovered normal fully.

7. NO obviously descends in the myocardiac cardiac muscle of Tiroidina disposition, and medicine 0213 makes and rises 68%, (p＜0.01).

8. myocardial cell's apoptosis rate reaches 97.5% (p＜0.01) in the Tiroidina disposition myocardosis.Myocardiac myocardial cell's aneuploidy rate reaches 13.5%, makes the heteroploid completely dissolve after medicine 0213 treatment.

9. medicine 0213 treatment obviously improves the vascular lesion that is caused by thyroxine.

Several vascular lesions of myocardosis that 0213 pair of thyroxine heavy dose of brief summary endothelin antagonist causes have the obvious treatment effect, and prompting endothelin antagonist 0213 can be used for treating myocardosis, and hyperthyroidism.

7 medicines, 0214 treatment hypertension

DOCA added drink the hypertension that salt solution causes, the acute iv administration of medicine 0214 and chronic filling stomach make all that blood pressure obviously reduces in the DOCA hypertension model.

In the external document, reported many relevant endothelin-receptor antagonists treatment left heart failures (heart failure), pulmonary hypertension, bronchial asthma, subarachnoid hemorrhage waits experimental study and clinical study.At present, FDA has at first ratified Bosentan treatment pulmonary hypertension.The pulmonary arterial wall of pulmonary hypertension is loose and cause a little less than the right heart failure that the participation of endothelin mechanism is all arranged.The 0213 pair of left heart failure and pulmonary hypertension are all effective in cure.0213 pair of illness due to being increased by endothelin is effective, as myocardosis and the hyperfunction disease of thyroxine.The biological activity that more than is new endothelin antagonist 0213 compound is given an example.

Description of drawings

Fig. 1 is the experimental therapy figure that medicine 0213 of the present invention obviously improves rat acute heart failure (AHF) LVSP.

Fig. 2 is the LV+dp/dt that medicine 0213 of the present invention obviously improves rat acute heart failure (AHF) _MaxExperimental therapy figure.

Fig. 3 is the LV-dp/dt that medicine 0213 of the present invention obviously improves rat acute heart failure (AHF) _MinExperimental therapy figure.

Fig. 4 is the experimental therapy figure that medicine 0213 explanation pharmacological agent chronic heart failure rat of the present invention is disappeared myocardial remodelling.

Fig. 5 is the LV+dp/dt that medicine 0213 medicine of the present invention obviously improves failure heart _MaxExperimental therapy figure.

Fig. 6 is the LV-dp/dt that medicine 0213 medicine of the present invention obviously improves failure heart _MinExperimental therapy figure.

Fig. 7 is the experimental therapy figure that medicine 0213 medicine of the present invention obviously improves the LVDP of failure heart.

Fig. 8 is the experimental therapy figure that medicine 0213 medicine of the present invention reduces ET and ANP in the heart failure rat.

Fig. 9 is that medicine 0213 treatment chronic heart failure rat of the present invention is improved the experimental therapy figure that ANP mRNA expresses.

Figure 10 is that medicine 0213 treatment chronic heart failure rat of the present invention is improved preproET-1mRNA expression experimental therapy figure.

Embodiment

The following examples can make those skilled in the art more fully understand the present invention, but cannot limit the present invention by any way.

Embodiment

4-benzyloxy-2-hydroxy acetophenone

With 5g (0.033mol) 2, the 4-resacetophenone is dissolved in the 150ml acetone, adds 6.5g (0.05mol) K ₂CO ₃, 3g KI, 0.1g TBAB under agitation slowly splashes into 4.9g (0.039mol) benzyl chloride, and in room temperature reaction 0.5hr, back flow reaction 2hr is chilled to room temperature again, filter, the filtrate evaporate to dryness, remnants obtain white needle 5.6g, yield 70% with the dehydrated alcohol recrystallization.

4-(right-the chlorine benzyloxy)-2-hydroxy acetophenone

With 7.6g (0.05mol) 2, the 4-resacetophenone is dissolved in the 150ml acetone, adds 7g (0.05mol) K ₂CO ₃, 3g KI, 0.1g TBAB under agitation slowly splash into 7.7g (0.05mol) right-chlorobenzyl chloride, in room temperature reaction 0.5hr, back flow reaction 3hr is chilled to room temperature again, filters, the filtrate evaporate to dryness remainingly obtains white needle 10.4g, yield 75% with the dehydrated alcohol recrystallization.

2,4-two (right-the chlorine benzyloxy) methyl phenyl ketone

With 15.2g (0.1mol) 2,4-resacetophenone and 40g (0.25mol) be right-chlorobenzyl chloride, 55g (0.4mol) K ₂CO ₃, be blended among the 70ml DMF, in 50 ℃ of reaction 6hr, be chilled to room temperature, reaction solution is poured in the frozen water, and the solid of separating out gets the 24g white crystal with the dehydrated alcohol recrystallization, yield 60%.

1-benzyloxy-4-(right-the chlorine benzyloxy) methyl phenyl ketone

With 5g (0.018mol) 4-(right-the chlorine benzyloxy)-2-hydroxy acetophenone and 3g (0.025mol) benzyl chloride, 5g (0.036mol) K ₂CO ₃In 50 ℃ of reaction 5hr, be chilled to room temperature in 50ml DMF, pour in the frozen water, the solid of separating out gets 3.6g light brown needle, yield 56% with the dehydrated alcohol recrystallization.

2,4-two (right-the chlorine benzyloxy) phenacyl oxalic acid diethyl ester

With 23g (0.057mol) 2,4-two (right-the chlorine benzyloxy) methyl phenyl ketone is dissolved among the 80mlTHF, under 50 ℃, splash into the 100ml alcohol sodium solution of making by 18g (0.078mol) sodium Metal 99.5 that is dissolved with 13ml (0.09mol) oxalic acid diethyl ester, drip and finish, be warming up to back flow reaction 8hr, cooling, pour in the 500ml water that contains dense HCl, the solid filtering of separating out is used washing with alcohol, drying obtains 28g khaki color solid, yield 98%.

3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid, ethyl ester

With 2 of the above-mentioned preparation of 25g (0.05mol), 4-two (right-the chlorine benzyloxy) phenacyl oxalic acid diethyl ester is dissolved in the 200ml glacial acetic acid, slowly splashes into the hydrazine hydrate of 3.6g (0.06mol) 85%, drips to finish, back flow reaction 8hr, be chilled to room temperature, separate out white needle, filter, with HOAc recrystallization absolute ethanol washing, dry white powder solid 19.2g, yield 77%, mp:177-179 ℃ of getting. ¹HNMR(CDCl ₃)δ1.32(3H，t，-CO ₂CH ₂CH ₃)，4.28(2H，q.-CO ₂CH ₂CH ₃)，5.12(2H，s，4-OCH ₂Ar)，5.24(2H，s，2-OCH ₂Ar)，6.68(1H，d，J＝9.0，5-H)，6.79(1H，s，3-H)，7.03(1H，s，4’-H of pyrazole)，7.40-7.59(8H，m，-ArH)，7.71(1H，d，J＝8.6，6-H)，8.20(1H，s，-NH).

3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid, ethyl ester

With reference to the preparation method of 3-(2,4-two (right-the chlorine benzyloxy) phenyl)-pyrazoles-5-carboxylic acid, ethyl ester, get white solid, yield 72%, mp:137-138 ℃.

3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I01)

2g (4.3mmol) above-claimed cpd is dissolved among the 15mlTHF, add 25ml methyl alcohol and 10ml 10%KOH, back flow reaction 2hr, be chilled to room temperature, regulate pH=3 with 10%HCl, add the suitable quantity of water dilution, the solid filtering that obtains, obtain colourless particulate solid 1.0g, yield 53% with the DMF-EtOH recrystallization.mp：239-241℃.Anal.C ₂₄H ₁₉ClN ₂O ₄·0.5H ₂O.Calcd：C，64.94；H，4.51；N，6.31.Found：C，65.26；H，4.31；N.6.43.IR(KBr)ν3249，2866，1712，1614，1580，1493，1455，1410，1276，1301，1279，1239，1170，1058，1005，962，807，754，700cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ5.06(2H，s，4-OCH ₂Ar)，5.20(2H，s，2-OCH ₂Ph)，6.66(1H，d，J＝8.6，5-H)，6.70(1H，d，J＝2.0，3-H)，7.10(1H，s，4’-H of pyrazole)，7.34-7.45(9H，m，-PhH and ArH)，7.66(1H，d，J＝8.6，6-H).MS(EI)m/e：434(M ⁺+1)，343，125，91(100).

1-ethyl-3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid, ethyl ester

1g (2mmol) 3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid, ethyl ester is dissolved in the 20ml acetone, adds 2g (14mmol) K ₂CO ₃And the 1ml monobromethane, back flow reaction 2hr is chilled to room temperature, filters, and boils off an amount of acetone, adds methyl alcohol, separates out colourless needle 0.76g, yield 75%, mp:130-131 ℃.

1-ethyl-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid, ethyl ester

The preparation method of reference compound 1-ethyl-3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid, ethyl ester gets white needle, yield 81%, mp:95-96 ℃. ¹HNMR(CDCl ₃+DMSO-d ₆)δ1.34(3H，t，-CO ₂CH ₂CH ₃)，1.46(3H，t，-NCH ₂CH ₃)、4.30(2H，q，-CO ₂CH ₂CH ₃)，4.62(2H，q，-NCH ₂CH ₃)，5.01(2H，s，4-OCH ₂Ar)，5.06(2H，s，2-OCH ₂Ar)，6.58(1H，d，J＝2.1，3-H)，6.62(1H，dd，J＝2.1 and 9.0，5-H)，7.21(1H，s.4’-H of pyrazole)，7.28-7.51(8H，m，-ArH)，7.92(1H，d，J＝9.0，6-H).

1-methyl-3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I02)

The preparation of reference compound I03 gets white crystal, yield 61%.mp：203-204℃.Anal.C ₂₅H ₂₁ClN ₂O ₄.Calcd：C，66.89；H，4.68；N，6.24.Found：C，66.67；H，4.68；N，6.48.IR(KBr)ν 3029，2913，1696，1612，1586，1539，1489，1451，1283，1249，1184，1108，1013，810，767，700cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ4.20(3H，s，-NCH ₃)，5.03(2H，s，-OCH ₂-)，5.17(2H，s，-OCH ₂-)，6.61(1H，dd，J＝2.4 and 8.7，5-H)，6.63(1H，d，J＝2.3，3-H)，7.30(1H，s，4’-H of pyrazole)，7.31-7.46(9H，m，-ArH and PhH)，7.86(1H，d，J＝8.8，6-H).MS(EI)m/e：448(M ⁺+1)，403，357，125.91(100).

1-ethyl-3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I03)

0.55g (1mmol) above-claimed cpd 1-ethyl-3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid, ethyl ester is dissolved among 15ml THF and the 10ml MeOH, add 10ml 10%NaOH, back flow reaction 0.5hr, be chilled to room temperature, regulate pH=3 with 10%HCl, the solid that obtains gets white needle 0.35g, yield 64% with the dehydrated alcohol recrystallization.mp：200-201℃.Anal.C ₂₆H ₂₃ClN ₂O ₄.Calcd：C，67.46；H，4.97；N，6.05.Found：C，67.35；H，5.05；N，6.20.IR(KBr)ν2979，1694，1612，1587，1536，1451，1301，1281，1237，1183，1110，1060，1013，810，768，700cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ1.52(3H，t，-NCH ₂CH ₃)，4.69(2H，q，-NCH ₂CH ₃)，5.05(2H，s，4-OCH ₂Ar)，5.18(2H，s，2-OCH ₂Ph)，6.65-6.67(2H，m，3-H and 5-H)，7.26-7.47(10H，m，-ArH，PhH and 4’-H of pyrazole)，7.96(1H，d，J＝9.1，6-H).MS(EI)m/e：462(M ⁺+1)，417，337，125，91(100).

1-propyl group-3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I04)

The preparation of reference compound I03 gets white crystal, yield 50%.mp：182-184℃.Anal.C ₂₇H ₂₅ClN ₂O ₄.Calcd：C，68.00；H，5.25；N，5.88.Found：C，68.27；H，5.05；N，5.81.IR(KBr)ν3438，3032，2966，1693，1614，1585，1535，1453，1376，1290，1175，1126，1062，1015，810，739cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ0.96(3H，t，-NCH ₂CH ₂CH ₃)，1.91(2H，6，-NCH ₂CH ₂CH ₃)，4.56(2H，t，-NCH ₂CH ₂CH ₃)，5.03(2H，s，4-OCH ₂Ar)，5.16(2H，s，2-OCH ₂Ph)，6.62(1H，dd，J＝2.2 and 9.2，5-H)，6.64(1H，d，J＝2.1，3-H)，7.31-7.46(10H，m，-ArH，PhH and 4’-H of pyrazole)，7.91(1H，d，J＝9.1，6-H).MS(EI)m/e：476(M ⁺+1)，431，351，125，91(100).

1-butyl-3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I05)

The preparation of reference compound I03 gets white crystal, yield 88%.mp：170-172℃.Anal.C ₂₈H ₂₇ClN ₂O ₄.Calcd：C，68.50；H，5.50；N，5.71.Found：C，68.68；H，5.56；N，5.75.IR(KBr)ν2961，1693，1614，1540，1448，1288，1175，1125，1062，1015，812cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ0.93(3H，t，-CH ₂CH ₃)，1.37(2H，6，-N(CH ₂) ₂CH ₂CH ₃)，1.85(2H，5，-NCH ₂CH ₂CH ₂CH ₃)，4.60(2H，t，-NCH ₂(CH ₂) ₂CH ₃)，5.01(2H，s，4-OCH ₂Ar)，5.16(2H，s，2-OCH ₂Ph)，6.59-6.63(2H，m，3-H and 5-H)，7.29(1H，s，4’-H of pyrazole)，7.30-7.44(9H，m，-ArH and PhH)，7.89(1H，d，J＝9.2，6-H).MS(EI)m/e：490(M ⁺+1)，445，365，125，91(100).

1-(3-carboxyl propyl group)-3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I06)

The preparation of reference compound I03 gets white crystal, yield 75%.mp：202-203℃.Anal.C ₂₈H ₂₅ClN ₂O ₆.Calcd：C，64.55；H，4.80；N，5.38.Found：C，64.75；H，4.82；N，5.36.IR(KBr)ν3062，2937，1710，1692，1583，1540，1450，1292，1240，1171，1102，1016，810，768cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ2.21(2H，p，-NCH ₂CH ₂CH ₂CO ₂H)，2.35(2H，t，-N(CH ₂) ₂CH ₂CO ₂H)，4.67(2H，t，-NCH ₂-)，5.02(2H，s，-OCH ₂Ar)，5.16(2H，s，-OCH ₂Ph)，6.59-6.63(2H，m，3-H and 5-H)，7.30-7.43(10H，m，-ArH，PhH and H of pyrazole)，7.89(1H，d.J＝9.2，6-H).MS(EI)m/e：520(M ⁺+1)，476，351.125(100)，91.

1-benzyl-3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I07)

The preparation of reference compound I03 gets white crystal, yield 75%.mp：217-218℃.Anal.C ₃₁H ₂₅ClN ₂O ₄.Calcd：C，70.92；H，4.77；N，5.34.Found：C，70.86；H，4.67；N，5.28.IR(KBr)ν3031，2952，1691，1610，1582，1535，1452，1381，1295，1272，1183，1095，1012，822，768，717cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ5.05(2H，s，-OCH ₂Ar)，5.18(2H，s，-OCH ₂Ph)，5.81(2H，s，-NCH ₂Ph)，6.64-6.66(2H，m，3-H and 4-H)，7.26-7.46(10H，m，-ArH，PhH and4’-H of pyrazole)，7.99(1H，d，J＝9.3，6-H).MS(EI)m/e：524(M ⁺+1)，433，125，91(100).

1-(4-benzyl chloride base)-3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I08)

The preparation of reference compound I03 gets white crystal, yield 51%.mp：211-212℃.Anal.C ₃₁H ₂₄Cl ₂N ₂O ₄.Calcd：C，66.67；H，4.30；N，5.02.Found：C，66.47；H，4.36；N，5.19.IR(KBr)ν3027.1693，1613.1583，1492，1450，1292，1173，1092，1072，1016，810，696cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ5.02(2H，s，-OCH ₂Ar)，5.16(2H，s，-OCH ₂Ph)，5.77(2H，s，-NCH ₂Ar)，6.59-6.63(2H，m，3-H and 4-H)，7.23-7.43(14H，m，-ArH，PhH and4’-H of pyrazole)，7.92(1H，d，J＝9.0，6-H).MS(EI)m/e：558(M ⁺+1)，433，125，91(100).

3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I09)

The preparation method of reference compound I01 gets clear crystal, yield 82%.mp：236-238℃.Anal.C ₂₄H ₁₈Cl ₂N ₂O ₄.Calcd：C，61.41；H，3.84；N，5.97.Found：C，61.40；H，3.90；N，6.29.IR(KBr)ν3235，2896，1713，1614，1580，1492，1453，1408，1376，1279，1239，1171，1061，1005，963，801cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ2.65(1H，br，-NH)，5.06(2H，s，-OCH ₂Ar)，5.15(2H，s，-OCH ₂Ar)，6.65(1H，d，J＝2.3，3-H)，6.67(1H，d，J＝2.4 and 9.2，5-H)，7.09(1H，s，4’-H of pyrazole)，7.32-7.41(8H，m，-ArH)，7.65(1H，d，J＝9.3，6-H).MS(EI)m/e：468(M ⁺+1)，423，125(100).

1-methyl-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I10)

The preparation method of reference compound I03 gets white crystal, yield 71%.mp：205-206℃.Anal.C ₂₅H ₂₀Cl ₂N ₂O ₄.Calcd：C，61.98；H，4.13；N，5.79.Found：C，62.21；H，4.18；N，6.05.IR(KBr)ν1694.1615，1584，1539，1492，1450，1368，1293，1182，1116，1014，808，767cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ4.21(3H，s，-NCH ₃)，5.02(2H，s，-OCH ₂Ar)，5.12(2H，s，-OCH ₂Ar)，6.57(1H，d，J＝2.4，3-H)，6.63(1H，d，J＝2.4and 8.6，5-H)，7.28(1H，s，4’-H of pyrazole)，7.30-7.38(8H，m，-ArH)，7.86(1H，d，J＝8.6，6-H).MS(EI)m/e：482(M ^-+1)，437.357，313，125(100).

1-ethyl-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I11)

The preparation method of reference compound I03 gets white crystal, yield 90%.mp：192-193℃.Anal.C ₂₆H ₂₂Cl ₂N ₂O ₄.Calcd：C，62.78；H，4.43；N，5.63.Found：C，63.24；H，4.58；N，5.95.IR(KBr)ν2982，2877，1693，1578.1537，1492，1455，1408，1277，1182，1088，1054，1014，815cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ1.43(3H，t，-NCH ₂CH ₃)，4.59(2H，q，-NCH ₂CH ₃)，5.04(2H，s，-OCH ₂Ar)，5.13(2H，s，-OCH ₂Ar)，6.57-6.66(2H，m，3-H and5-H)，7.20(1H，s，4’-H of pyrazole)，7.27-7.45(8H，m，-ArH)，7.85(1H，d，J＝9.0，6-H).MS(EI)m/e：496(M ⁺+1)，423，371，327，125(100).

1-propyl group-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I12)

The preparation method of reference compound I03 gets white crystal, yield 83%.mp：184-186℃.Anal.C ₂₇H ₂₄Cl ₂N ₂O ₄.Calcd：C，63.41；H，4.70；N，5.48.Found：C，63.52；H，4.75；N，5.73.IR(KBr)ν2966，2935，1692，1614，1584，1539，1491，1452，1376，1286，1178，1123，1087，1061，1014，810，767cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ0.96(3H，t，-N(CH ₂) ₂CH ₃)，1.93(2H，h，-NCH ₂CH ₂CH ₃)，4.58(2H，t，-NCH ₂CH ₂CH ₃)，5.05(2H，s，-OCH ₂Ar)，5.14(2H，s，-OCH ₂Ar)，6.60(1H，d，J＝2.3，3-H)，6.65(1H，dd，J＝2.3 and 8.6，5-H)，7.29(1H，s，4’-H of pyrazole)，7.34-7.41(8H，m，-ArH)，7.89(1H，d，J＝8.5，6-H).MS(EI)m/e：510(M ⁺+1)，466，385，125(100).

1-butyl-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I13)

The preparation method of reference compound I03 gets white crystal, yield 78%.mp：164-165℃.Anal.C ₂₈H ₂₆Cl ₂N ₂O ₄.Calcd：C，64.00；H，4.95；N，5.33.Found：C，63.62；H，5.13；N，5.40.IR(KBr)ν2960，2872，1692，1614，1583，1492，1451，1375，1283，1179，1120，1090，1015，810cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ0.93(3H，t，-N(CH ₂) ₃CH ₃)，1.34(2H，h，-NCH ₂CH ₂CH ₂CH ₃)，1.84(2H，p，-NCH ₂CHH ₂CH ₂CH ₃)，4.57(2H，t，-NCH ₂(CH ₂) ₂CH ₃)，5.00(2H，s，-OCH ₂Ar)，5.09(2H，s，-OCH ₂Ar)，6.56-6.62(2H，m，3-H and 5-H)，7.23(1H，s，4’-H of pyrazole)，7.30-7.45(8H，m，-ArH)，7.87(1H，d，J＝9.0，6-H).MS(EI)m/e：524(M ⁺+1)，480，399，355，125(100).

1-carboxymethyl-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I14)

The preparation method of reference compound I03 gets white crystal, yield 33%.mp：210-212℃.Anal.C ₂₆H ₂₀Cl ₂N ₂O ₆.Calcd：C，59.20；H，3.80；N，5.31.Found：C，59.17；H，3.92；N，5.72.IR(KBr)ν 2952，1735，1695，1614，1583，1492，1450，1408，1292，1257，1176，1092，1015，830，806cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ5.02(2H，s，-OCH ₂Ar)，5.12(2H，s，-OCH ₂Ar)，5.34(2H，s，-NCH ₂CO ₂H)，6.58(1H，d，J＝2.0，3-H)，6.61(1H，dd，J＝2.0 and8.5，5-H)，7.32-7.39(9H，m，-ArH and 4’-H of pyrazole)，7.87(1H，d，J＝8.4，6-H).MS(EI)m/e：526(M ⁺+1)，482，401，357，125(100).

1-(3-carboxyl propyl group)-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I15)

The preparation method of reference compound I03 gets white crystal, yield 63%.mp：202-204℃.Anal.C ₂₈H ₂₄Cl ₂N ₂O ₆.Calcd：C，60.54；H，4.32；N，5.05.Found：C，60.53；H，4.53；N，5.31.IR(KBr)ν3036，2930，1691，1613，1583，1537，1492，1452，1288，1232，1171，1097，1016，811cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ2.20(2H，p，-NCH ₂CH ₂CH ₂CO ₂H)，2.34(2H，t，-N(CH ₂) ₂CH ₂CO ₂H)，4.66(2H，t，-NCH ₂(CH ₂) ₂CO ₂H)，5.02(2H，s，-OCH ₂Ar)，5.11(2H，s，-OCH ₂Ar)，6.57(1H，d，J＝2.2，3-H)，6.62(1H，dd，J＝2.2and 8.7，5-H)，7.27(1H，s，4’-H of pyrazole)，7.31-7.39(8H，m，-ArH)，7.87(1H，d，J＝8.5，6-H).MS(EI)m/e：554(M ⁺+1)，510，430，385，125(100).

1-(2-bromotrifluoromethane)-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I16)

The preparation method of reference compound I03 gets white crystal, yield 71%.mp：190-191℃.Anal.C ₂₆H ₂₁BrCl ₂N ₂O ₄.Calcd：C，54.17；H，3.65；N，4.86.Found：C，54.07；H，3.43；N，4.88.IR(KBr)ν3027，2952，2874，1693，1614，1585，1492，1452，1407，1294，1178，1091，1014，807，766cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ4.04(2H，t，-CH ₂Br)，4.77(2H，t，-NCH ₂-)，5.03(2H，s，-OCH ₂Ar)，5.12(2H，s，-OCH ₂Ar)，6.59(1H，d，J＝2.4，3-H)，6.63(1H，dd，J＝2.4 and 8.4，5-H)，7.30(1H，s，4’-H of pyrazole)，7.32-7.36(8H，m，-ArH)，7.86(1H，d，J＝8.6，6-H).MS(EI)m/e：574(M ⁺+1)，494，422，369，125(100).

1-(2-tetramethyleneimine-1-yl) ethyl-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I17)

The preparation method of reference compound I03 gets white crystal, yield 88%.mp：227-228℃.Anal.C ₃0H ₁₉Cl ₂N ₃O ₄.Calcd：C，63.60；H，5.12；N，7.42.Found：C，63.47；H，5.33；N，7.49.IR(KBr)ν3655，3395，1610，1581，1533，1493，1453，1405，1376，1297，1183，1088，1012，814，789cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ1.46-2.07(4H，br，-CH ₂(CH ₂) ₂CH ₂-of pyrrolidine)，2.20(4H，br，-CH ₂(CH ₂) ₂CH ₂- of pyrrolidine)，3.71(2H，t，-NCH ₂CH ₂-pyrrrolidine)，5.07(2H，s，-OCH ₂Ar)，5.20(2H，s，-OCH ₂Ar)，5.26(2H，t，-NCH ₂CH ₂-pyrrolidine)，6.60(1H，d，J＝2.1，3-H)，6.67(1H，dd，J＝2.3 and 8.6，5-H)，7.28(1H，s，4’-H of pyrazole)，7.34-7.44(8H，m，-ArH)，7.86(1H，d，J＝8.6，6-H).MS(EI)m/e：565(M ⁺+1)，125，97，84(100).

1-allyl group-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I18)

The preparation method of reference compound I03 gets white crystal, yield 75%.mp：190-192℃.Anal.C ₂₇H ₂₂Cl ₂N ₂O ₄.Calcd：C，63.65；H，4.32；N，5.50.Found：C，63.51；H，4.26；N，5.57.IR(KBr)ν2877，1692，1610，1578，1536，1492，1456，1408，1275，1182，1093，1014，938，813cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ5.02(2H，s，-OCH ₂Ar)，5.11(2H，s，-OCH ₂Ar)，5.09-5.18(2H，m，-CH＝CH ₂)，5.23(2H，d，J＝5.58，-NCH ₂CH＝CH ₂)，6.08(1H，m，-CH＝CH ₂)，6.58(1H，d，J＝2.3，3-H)，6.62(1H，dd，J＝2.3 and 8.5，5-H)，7.29(1H，s，4’-Hof pyrazole)，7.31-7.38(8H，m，-ArH)，7.87(1H，d，J＝8.4，6-H).MS(EI)m/e：508(M ⁺+1)，464，383，125(100).

1-phenyl-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I19)

The preparation method of reference compound I03 gets white crystal, yield 66%.mp：206-208℃.Anal.C ₃₀H ₂₂Cl ₂N ₂O ₄.Calcd： _C，66.06； _H，4.04； _N，5.14.Found： _C，65.67； _H，4.45； _N，5.13.IR(KBr)ν 2919，1697，1617，1555，1492，1451，1372，1311，1230，1181，1127，1015，812，776.694cm ^-1； ¹HNMR(CDCl ₃)δ5.05(2H，s，-OCH ₂Ar)，5.16(2H，s，-OCH ₂Ar)，6.64-6.66(2H，m，3-H and 5-H)，7.28-7.55(9H，m，ArH and 4’-H of pyrazole)，7.98(1H，d，J＝8.1.6-H).MS(EI)m/e：544(M ⁺+1)，500，375，125(100).

1-benzyl-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I20)

The preparation method of reference compound I03 gets white crystal, yield 87%.mp：187-188℃.Anal.C ₃₁H ₂4Cl ₂N ₂O ₄·0.5H ₂O.Calcd：C，65.49；H，4.40；N，4.93.Found：C，65.11；H，4.24；N.5.09.IR(KBr)ν3030，2948，2867，1695，1612，1582，1541，1493，1450，1282，1178，1095，1015，811，722cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ5.03(2H，s，-OCH ₂Ar)，5.11(2H，s，-OCH ₂Ar)，5.82(2H，s，-NCH ₂Ph)，6.58(1H，d，J＝2.3，3-H)，6.62(1H，dd，J＝2.3and 8.6，5-H)，7.22-7.38(14H，m，-PhH，ArH and 4’-H of pyrazole)，7.91(1H，d，J＝8.5，6-H).MS(EI)m/e：558(M ⁺+1)，467，433，389，125(100)，91.

1-(4-benzyl chloride base)-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I21)

The preparation method of reference compound I03 gets white crystal, yield 98%.mp：233-234℃.Anal.C ₃₁H ₂₃Cl ₃N ₂O ₄.Calcd：C，62.68；H，3.88；N，4.72.Found：C，63.03；H，3.94；N，5.07.IR(KBr)ν 3031，2954，1692，1614，1586，1492，1454，1408，1279，1184，1093，1015，811，748cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ5.03(2H，s，-OCH ₂Ar)，5.11(2H，s，-OCH ₂Ar)，5.77(2H，s，-NCH ₂Ar)，6.58(1H，d，J＝2.3，3-H)，6.62(1H，dd，J＝2.3 and 8.5，5-H)，7.24-7.41(13H，m.-ArH and 4’-H of pyrazole)，7.90(1H，d，J＝8.5，6-H).MS(EI)m/e：592(M ⁺+1)，467，125(100)，91.

1-benzyl-3-(2,4-two (to the fluorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I22)

The preparation method of reference compound I03 gets white crystal, yield 68%.mp：203-204℃.Anal.C ₃₁H ₂₄F ₂N ₂O ₄.Calcd：C，70.71；H，4.59；N，5.32.Found：C，70.29；H，4.12；N，5.97.

1-benzyl-3-(2,4-two (adjacent iodine benzyloxy) phenyl) pyrazoles-5-carboxylic acid (I23)

The preparation method of reference compound I03 gets white crystal, yield 82%.mp：197-198℃.Anal.C ₃₁H ₂₄I ₂N ₂O ₄.Calcd：C，50.16；H，3.26；N，3.77.Found：C，50.58；H，3.77；N，4.12.

1-ethyl-3-(the adjacent bromo-benzyloxy-of 2-, 4-is to the iodine benzyloxy) phenyl-pyrazole-5-carboxylic acid (I24)

The preparation method of reference compound I03 gets white crystal, yield 84%.Mp:200-201 ℃ of .Anal.C ₂₆H ₂₂Cl ₂N ₂O ₄.Calcd:C, 49.31; H, 3.50; N, 4.42.Found:C, 49.80; H, 3.78; N, 4.88.1-ethyl-3-(the adjacent chlorine benzyloxy of 2-, 4-is to bromo-benzyloxy-) phenyl-pyrazole-5-carboxylic acid (I25)

The preparation method of reference compound I03 gets white crystal, yield 79%.mp：198-199℃.Anal.C ₂₆H ₂₂Cl ₂N ₂O ₄.Calcd：C，57.63；H，4.09；N，5.17.Found：C，58.01；H，4.41；N，5.45.

1-methyl-5-(2-benzyloxy-4-(4-chlorine benzyloxy) phenyl) pyrazoles-3-carboxylic acid (I26)

The preparation method of reference compound I03 gets white crystal, yield 89%.mp：148-150℃.Anal.C ₂₅H ₂₁ClN ₂O ₄.Calcd：C，66.89；H，4.68；N，6.24.Found：C，66.53；H，4.98；N，6.46.IR(KBr)ν 3029，2897，1693，1615，1580，1556，1491，1452，1372，1306，1250，1173，1117，1012，807.731，694cm ^-1； ¹HNMR(CDCl ₃+DMSO-d ₆)δ3.72(3H，s，-NCH ₃)，5.11(2H，s，-OCH ₂Ar)，5.12(2H，s，-OCH ₂Ar)，6.65(1H，s，4’-H of pyrazole)，6.68(1H，dd，J＝2.1 and 8.5，5-H)，6.80(1H，d，J＝2.1，3-H)，7.19(1H，d，J＝8.4，6-H)，7.26-7.33(5H，m，-PhH)，7.37-7.46(4H，m，-ArH).MS(EI)m/e：448(M ⁺+1)，404，125，91(100).

1-phenyl-5-(2,4-two (4-chlorine benzyloxy) phenyl) pyrazoles-3-carboxylic acid (I27)

The preparation method of reference compound I03 gets white crystal, yield 67%.mp：205-206℃.Anal.C ₃₀H ₂₂Cl ₂N ₂O ₄·0.5H ₂O.Calcd：C，67.15；H，3.97；N，5.05.Found：C，67.13；H，4.23；N，5.53.IR(KBr)ν3067，2922，2872，1705，1614，1585，1538，1493，1445，1374，1298，1243，1180，1117，1069，1013，801，767cm ^-1； ¹HNMR(CDCl ₃)δ4.67(2H，s，-OCH ₂Ar)，5.01(2H，s，-OCH ₂Ar)，6.41(1H，d，J＝2.2，3-H)，6.61(1H，dd，J＝2.2 and 8.5，5-H)，6.86(1H，d，J＝8.4，6-H)，7.02(1H，s，4’-H of pyrazole)，7.23-7.40(13H，m，-PhH and ArH).MS(EI)m/e：544(M ⁺+1)，125(100).

1-phenyl-3-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid, ethyl ester (8) and 1-phenyl-5-(2,4-two (right-the chlorine benzyloxy) phenyl) pyrazoles-3-carboxylic acid, ethyl ester (9)

With 1.5g (3mmol) 2,4-two (right-the chlorine benzyloxy) phenacyl oxalic acid diethyl ester is dissolved among the 20ml HOAc, slowly splashes into 0.4g (3.5mmol) phenylhydrazine, drip complete back flow reaction 10hr, be chilled to room temperature, reaction solution is poured in the frozen water, extracts with chloroform 3 * 10ml, anhydrous magnesium sulfate drying, boil off chloroform, (elutriant is a sherwood oil to remaining rapid column chromatography: ethyl acetate=1: 1 (v/v)) get compound 8 and be white needle 0.06g, yield 3.4%, mp:121-122 ℃ ¹HNMR (CDCl ₃) δ 1.24 (3H, t ,-CO ₂CH ₂CH ₃), 4.22 (2H, q ,-CO ₂CH ₂CH ₃), 5.04 (2H, s ,-OCH ₂Ar), 5.13 (2H, s ,-OCH ₂Ar), 6.63-6.66 (2H, m, 3-H and 5-H), 7.36-7.49 (14H, m ,-PhH, ArH and 4 '-H of pyrazole), 8.01 (1H, d, J=8.8,6-H). and compound 9 is the about 0.7g of white needle, yield 39%, and mp:137-138 ℃, ¹HNMR (CDCl ₃) δ 1.42 (3H, t ,-CO ₂CH ₂CH ₃), 4.44 (2H, q ,-CO ₂CH ₂CH ₃), 4.65 (2H, s ,-OCH ₂Ar), 4.98 (2H, s ,-OCH ₂Ar), 6.38 (1H, d, J=2.3,3-H), 6.58 (1H, dd, J=2.3 and 8.4,5-H), 6.83 (1H, d, J=8.4,6-H), 6.95 (1H, s, 4 '-H ofpyrazole), 7.19-7.37 (13H, m ,-PhH and ArH).

1-methyl-3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid, ethyl ester (11a) and 1-methyl-5-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-3-carboxylic acid, ethyl ester (12a)

With 0.8g (1.7mmol) 3-(2-benzyloxy-4-(right-the chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid, ethyl ester and 1mlCH ₃I, 3g K ₂CO ₃, be mixed in back flow reaction 2hr in the 25ml acetone, be chilled to room temperature, filter, boil off acetone, remaining rapid column chromatography (elutriant is a sherwood oil: ethyl acetate=4: 1 (v/v)) getting compound 11a is white crystal 0.38g, yield 46%, and mp:139-140 ℃, ¹HNMR (CDCl ₃) δ 1.34 (3H, t ,-CO ₂CH ₂CH ₃), 4.21 (3H, s ,-NCH ₃), 4.30 (2H, q ,-CO ₂CH ₂CH ₃), 5.03 (2H, s ,-OCH ₂-), 5.14 (2H, s ,-OCH ₂-), 6.63 (1H, dd, J=2.4 and 8.8,5-H), 6.64 (IH, d, J=2.4,3-H), 7.29 (1H, s, 4 '-H ofpyrazole), (7.33-7.47 9H, m ,-PhH and ArH), 7.91 (1H, d, J=8.8,6-H). compound 12a is white crystal 0.34g, yield 41%, mp:124-126 ℃. ¹HNMR(CDCl ₃)δ1.41(3H，t，-CO ₂CH ₂CH ₃)，3.76(3H，s，-NCH ₃)，4.42(2H，q，-CO ₂CH ₂CH ₃)，5.04(2H，s，-OCH ₂-)，5.05(2H，s，-OCH ₂-)，6.62(1H，dd，J＝2.4 and 8.4，5-H)，6.68(1H，d，J＝2.3，3-H)，6.77(1H，s，4’-H ofpyrazole)，7.17(1H，d，J＝8.3，6-H)，7.21-7.37(9H，m，-PhH and ArH).

1-(4-benzyl chloride base)-3-(2-benzyloxy-4-(4-chlorine benzyloxy) phenyl) pyrazoles-5-carboxylic acid, ethyl ester (11b) and 1-(4-benzyl chloride base)-5-(2-benzyloxy-4-(4-chlorine benzyloxy) phenyl) pyrazoles-3-carboxylic acid, ethyl ester (12b)

The preparation method of reference compound 11a and 12a, getting compound 11b is white needle, yield 89%, mp124-126 ℃, ¹HNMR (CDCl ₃) δ 1.28 (3H, t ,-CO ₂CH ₂CH ₃), 4.24 (2H, q ,-CO ₂CH ₂CH ₃), 5.04 (2H.s ,-OCH ₂-), 5.14 (2H, s ,-OCH ₂-), 5.74 (2H, s, 1-NCH ₂Ar), 6.62-6.65 (2H, m.3-H and 5-H), 7.23-7.46 (14H, m ,-PhH, ArH and 4 '-H of pyrazole), 7.97 (1H, d, J=8.3,6-H). and compound 12b is white needle, yield 9.6%, and mp117-118 ℃, ¹HNMR (CDCl ₃) δ 1.41 (3H, t ,-CO ₂CH ₂CH ₃), 4.43 (2H, q ,-CO ₂CH ₂CH ₃), 4.95 (2H, s ,-OCH ₂-), 5.02 (2H, s ,-OCH ₂-), 5.23 (2H, s ,-NCH ₂Ar), 6.53 (1H, dd, J=2.4 and 8.4,5-H), 6.62 (1H, d, J=2.3,3-H), 6.79 (1H, s, 4 '-H of pyrazole), 6.97 (1H, d, J=8.4,6-H), 6.81-7.33 (13H, m ,-PhH and ArH).

Claims (10)

1. included compound and its esters of formula (I):

Wherein, R ₁Be C ₁-C ₆Alkyl or alkenyl, or have one to four carbon atom carboxylic acid or its ester class at interval, or have one to four carbon atom aryl or substituted aryl at interval, or have one to four carbon atom heterocycle at interval; R ₂, R ₃Be H or halogen independently of one another.

2. according to the described compound of claim 1, wherein R ₁Be C ₁-C ₄Alkyl, R ₂, R ₃Be 4-chlorine independently of one another.

3. according to the described compound of claim 2, wherein R ₁Be normal-butyl, R ₂, R ₃Be 4-chlorine independently of one another.

4. according to the described compound of claim 1, wherein R ₁Be one to two carbon atom carboxylic acid at interval, R ₂, R ₃Be 4-chlorine independently of one another.

5. according to the described compound of claim 4, wherein R ₁Be carboxymethyl, R ₂, R ₃Be 4-chlorine independently of one another.

6. pharmaceutical composition wherein contains general formula (I) compound and the pharmaceutical carrier of claim 1.

7. the general formula of claim 1 (I) the compound application that is used for preparing the medicine for the treatment of cardiovascular and cerebrovascular diseases as endothelin-receptor antagonists.

8. the general formula of claim 1 (I) compound is used for preparing the application of the medicine for the treatment of diabetes, ephrosis as endothelin-receptor antagonists.

9. the general formula of claim 1 (I) the compound application that is used for preparing the medicine for the treatment of asthma as endothelin-receptor antagonists.

10. the general formula of claim 1 (I) compound is used for preparing the application of the hyperfunction medicine of treatment Tiroidina as endothelin-receptor antagonists.

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