CN101899058B - Method for preparing thiazolopyrimidine compound, thiazolopyrimidine compound and application thereof - Google Patents
Method for preparing thiazolopyrimidine compound, thiazolopyrimidine compound and application thereof Download PDFInfo
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- CN101899058B CN101899058B CN2010101796316A CN201010179631A CN101899058B CN 101899058 B CN101899058 B CN 101899058B CN 2010101796316 A CN2010101796316 A CN 2010101796316A CN 201010179631 A CN201010179631 A CN 201010179631A CN 101899058 B CN101899058 B CN 101899058B
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- pyrimidine
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- OWJWDQPRPYNPFX-UHFFFAOYSA-N NC1CCN(Cc(cc2)cc(C#N)c2F)CC1 Chemical compound NC1CCN(Cc(cc2)cc(C#N)c2F)CC1 OWJWDQPRPYNPFX-UHFFFAOYSA-N 0.000 description 2
- YFSSAUWKOJDCKK-UHFFFAOYSA-N CC(C)(C)OC(NC1CCN(Cc(cc2)cc(C#N)c2F)CC1)=O Chemical compound CC(C)(C)OC(NC1CCN(Cc(cc2)cc(C#N)c2F)CC1)=O YFSSAUWKOJDCKK-UHFFFAOYSA-N 0.000 description 1
- CKXZPVPIDOJLLM-UHFFFAOYSA-N CC(C)(C)OC(NC1CCNCC1)=O Chemical compound CC(C)(C)OC(NC1CCNCC1)=O CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- MOFRJTLODZILCR-UHFFFAOYSA-N N#Cc1cc(C=O)ccc1F Chemical compound N#Cc1cc(C=O)ccc1F MOFRJTLODZILCR-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a novel method for preparing a thiazolopyrimidine compound and application thereof. The chemical name of the compound is 5-((4-(2-dichlorothiazolo[5,4-d]pyridine-7-amido)piperidine-1-radix)-2-fluorobenzonitrile mono-fumarate with the structural formula as shown in the specification. The thiazolopyrimidine compound is used for treatment of pulmonary hypertension, including hypoxic pulmonary hypertension.
Description
Technical field
The present invention relates to a kind of thiazole and pyrimidine compound, be used for pulmonary hypertension, comprise the treatment of Hypoxic Pulmonary Hypertension in Rats.The invention belongs to pharmaceutical chemistry and clinical application field.
Background technology
(Pulmonary Arterial Hypertension, PAH) being one type, to increase with carrying out property of PVR pulmonary vascular resistance be characteristics to pulmonary hypertension, finally causes right heart failure even dead extreme malignant progression property disease.Mainly show as exertional dyspnea clinically, breathe hard, weak, pectoralgia, faint etc.The pathogenic factor of pulmonary hypertension comparatively complicacy and precise mechanism is not also illustrated fully; The all generation effects in the pathogenic process of pulmonary hypertension of environmental factors, inherited genetic factors and other factors; These factors cause cardiovascular 26S Proteasome Structure and Function to change; Mainly involve the pulmonary artery and the right heart, show as the right ventricle plumpness, the right atrium expansion.The main pulmonary artery expansion, the lung arteriole is sparse on every side.Lung arteriole endotheliocyte, smooth muscle cell proliferation hypertrophy, the tunica intima fibrosis thickens, middle pachyhymenia, luminal stenosis, obturation, torsional deformation is clump shape and changes.Average age of onset is 36 years old, and 75% patient concentrates on 20～40 years old age bracket, also has 15% patient age below 20 years old.Patients with pulmonary hypertension 75% patient dies from 5 years after the diagnosis, and mean survival time (MST) was 1.9 years after symptom occurred; The right heart failure shower is arranged, and the mean survival time was less than 1 year.Its prognosis is catastrophic, we can say, this disease is exactly the cancer in the cardiovascular disorder, still lacks the efficacious therapy scheme at present.
Traditional medical treatment of pulmonary hypertension mainly is to the formation of right heart insufficiency and pulmonary artery primary thrombus, comprises oxygen uptake, diuresis, cardiac stimulant and anti-freezing.In addition, some medicines and treat-ment also are applied to clinical, and patient's quality of life and clinical prognosis are constantly improved.These medicines have: calcium ion antagonist (only 10% patient is effective); Prostacyclin class medicine (prostaglin X, UT-15, shellfish prostacyclin, Ilomedin ring element); Endothelium rope receptor antagonist (bosentan, An Beishengtan, Sai Tashengtan); Phosphodiesterase-5 (PDE-5) suppressor factor (Virga, Tadalafei); Rho SU11752 (fasudil); And the statins SV of studying maximum treatment PAH at present.Outside the medicine, new therapys such as gene therapy in recent years, live body lung transplantation, interatrial septum fistulization also constantly occur, and that is to say for pulmonary hypertension, multiple treatment means has been arranged now.
Yet, however, at present after various clinically medicines and the treat-ment application all the limiting factor of various degrees (curative effect is undesirable, the life-time service erious adverse reaction, cost an arm and a leg, route of administration inconvenience etc.As only 10% patient is effective after the calcium ion antagonist application, and have only acute lung vasodilation test male patient could use the calcium channel blocker treatment; Whether it is short that Virga is used to treat the pulmonary hypertension time, and the effect that suppresses phosphodiesterase 6 is arranged, and possibly cause irreversible renal impairment, can life-time service still disputable at present; Prostacyclin class preparation needs intravenous applications, subcutaneous injection or inhaled medication mostly, and route of administration is relatively not too convenient; The heavy dose use of endothelium rope receptor antagonist can cause the infringement of liver function), pulmonary hypertension does not have the special efficacy cure method at present.
Deepening continuously of PAH pathogenesis research, wide prospect has been opened up in treatment to PAH.Serotonin (5-HT) is proposed in nineteen fifty-five as a kind of vaso-active substance first; Extensively be present in the animal body; Especially at cardiovascular systems, remove sub-fraction and reuptaked and be stored in the thrombocyte China and foreign countries, nearly all 5-HT is all by the endotheliocyte deactivation of liver and lungs.5-HT is through producing various biological effects with its receptors bind; The 5-HT sorting technique of accepting extensively at present is that its acceptor is divided into 7 types; Wherein the 5-HT2 acceptor is divided into 5-HT2A, 2B, 2C; Be a member of G protein receptor super large family, mainly be distributed in tissue and organs such as vessel wall, vascular endothelial cell, thrombocyte, kidney.For many years, the 5-HT system has with the physiopathology of pulmonary hypertension always and involves, and some study prompting: the 5-HT2 receptor antagonist can be specifically and the 5-HT2 receptors bind, suppresses the effect of 5-HT, brings into play a series of biological effects.Especially protect, prevent that the research of aspects such as vascular smooth muscle hyperplasia, coronary heart disease from enjoying medical worker to pay close attention at blood vessel endothelium.Current; There are several kinds of serotonins (5-HT) receptor antagonist and serotonin transporter retarding agent studying and are used for PAH; Although these clinical trials are not all also accomplished; The medicine that does not have temporarily listing, but the research focus of relevant new drug development research having become PAH treatment has important clinical and realistic meaning.
Summary of the invention
Technical problem to be solved by this invention is: synthetic a kind of thiazole and pyrimidine compound, this compound is used for pulmonary hypertension (comprising the treatment of Hypoxic Pulmonary Hypertension in Rats) has good curative effect.
The present invention solves this technical problem the technical scheme that is adopted: a kind of thiazole and pyrimidine compound; Its chemical name is a 5-((4-(2-diuril azoles also [5; 4-d] pyrimidine-7-amino) piperidines-1-yl) methyl)-2-fluorobenzonitrile list fumarate (1), its structural formula is following:
The preparation method of above-claimed cpd, its synthetic route is following:
Operation steps is: with 4-tertiary butyl carbamate piperidines and 2-fluoro-5-formyl radical benzene nitrile is raw material; Under sodium triacetoxy borohydride and acetic acid effect, synthetic 1-(3-cyanic acid-4-luorobenzyl)-4-tertiary butyl carbamate piperidines adds TFA-DCM then and further reacts; The protection of sloughing amino obtains 5-((4-amino piperidine-1-yl) methyl)-2-fluorobenzonitrile; With product and 2,7-2-diuril azoles also [5,4-d] pyrimidine at p-MeC
6H
4SO
3React under the condition that H exists, generate 5-((4-(2-diuril azoles also [5,4-d] pyrimidine-7-is amino) piperidines-1-yl) methyl)-2-fluorobenzonitrile, obtain single fumarate with the fumaric acid reaction then.
The application of last above-claimed cpd 5-((4-(2-diuril azoles also [5,4-d] pyrimidine-7-is amino) piperidines-1-yl) methyl)-2-fluorobenzonitrile list fumarate: as the control of pulmonary hypertension.
Set up pulmonary hypertension rat model and hypoxic pulmonary hypertension rat model that Monocrotaline (MCT) brings out, adopt PowerLab/4SP systems measurement mean pulmonary arterial pressure (mPAP) and average right ventricular pressure (mRVP) etc. in integral level; After above-mentioned experimentation on animals finishes, get blood and put to death rat immediately, cut the thoracic cavity open and take out heart, lungs; Get inferior lobe of right lung and put into fixing 1 week of 10% Superlysoform, the gradient ethanol dehydration is got the same area lung tissue, right ventricle is processed sample; Paraffin embedding; Conventional section, the dyeing of Hematorylin Yihong, opticmicroscope is observed right ventricle thickness, cellular form, lung tissue and lung arteriole morphological change down.Through above experiment, estimate the intervention effect of above-claimed cpd (test-compound) to PAH.Find that test-compound 5-((4-(2-diuril azoles also [5,4-d] pyrimidine-7-is amino) piperidines-1-yl) methyl)-2-fluorobenzonitrile list fumarate has the pulmonary hypertension rat that good control Monocrotaline (MCT) brings out and the effect of hypoxic pulmonary hypertension.
The invention has the beneficial effects as follows: compound 5-of the present invention ((4-(2-diuril azoles also [5; 4-d] pyrimidine-7-amino) piperidines-1-yl) methyl)-2-fluorobenzonitrile list fumarate; Structure design is novel, synthetic route is rationally feasible, and step is simple, mild condition, yield are higher.Compound 5-of the present invention ((4-(2-diuril azoles also [5; 4-d] pyrimidine-7-is amino) piperidines-1-yl) methyl)-2-fluorobenzonitrile list fumarate has the activity of better control pulmonary hypertension; See embodiment 2 and 3 for details, yet these data are not as the restriction of claim of the present invention.
Embodiment
Below in conjunction with specific embodiment, the present invention is elaborated.
Enumerate exemplary embodiments below, the present invention is further specified, but be not construed as limiting the invention in any form.
Embodiment 1
The first step mixing 4-tertiary butyl carbamate piperidines (10mmol) and 2-fluoro-5-formyl radical benzene nitrile (10mmol) add sodium triacetoxy borohydride (15mmol) and acetic acid (20mmol) then in the 40ml methylene dichloride, logical N
2Reaction.Suspension at room temperature stirs behind the 16h and stops with sodium hydroxide solution, product use ethyl acetate extraction, use anhydrous sodium sulfate drying, obtain 1-(3-cyanic acid-4-luorobenzyl)-4-tertiary butyl carbamate piperidines after the solvent evaporated, productive rate is 85-95%.
Second 1-(3-cyanic acid-4-luorobenzyl)-4-tertiary butyl carbamate piperidines of obtaining of step joins in trifluoroacetic acid-methylene dichloride of 25%; At room temperature react 3h and slough protection amino; Volatilize solvent, add ETHYLE ACETATE, filter; Wash for several times with ETHYLE ACETATE, vacuum-drying obtains 5-((4-amino piperidine-1-yl) methyl)-2-fluorobenzonitrile.
The 3rd step 5-((4-amino piperidine-1-yl) methyl)-2-fluorobenzonitrile (1mmol) is dissolved in acetonitrile, fills N
2Protection adds 2, and 7-dichloro thiazole is [5,4-d] pyrimidines (1mmol) also, add p-MeC again
6H
4SO
3H is in 125 ℃ of reaction 2h.Be dissolved in the 20ml ETHYLE ACETATE after the reaction solution evaporation; Add 10ml sodium hydrogencarbonate and 10ml sodium chloride solution mixing again; Organic layer adds anhydrous sodium sulfate drying, concentrates the back and uses purification by silica gel column chromatography, obtains 5-((4-(2-diuril azoles also [5; 4-d] pyrimidine-7-amino) piperidines-1-yl) methyl)-the 2-fluorobenzonitrile, productive rate is 40-50%.
The 4th above-mentioned product of step (1mmol) is dissolved in the 1ml methylene dichloride, and the fumaric acid that adds 2M then and ETHYLE ACETATE 10ml be in 0 ℃ of reaction 1h, and filtering-depositing also washs with ETHYLE ACETATE, obtains single fumarate after the vacuum-drying, and productive rate is 80-90%.To have proved conclusively the structure of this product be 5-((4-(2-diuril azoles also [5,4-d] pyrimidine-7-is amino) piperidines-1-yl) methyl)-2-fluorobenzonitrile list fumarate to method through the POP.
Embodiment 2
The preventive and therapeutic effect of the pulmonary hypertension that test-compound [5-((4-(2-diuril azoles also [5,4-d] pyrimidine-7-is amino) piperidines-1-yl) methyl)-2-fluorobenzonitrile list fumarate] brings out Monocrotaline:
Rat gives disposable celiac injection 2%MCT (dosage 60mgkg-1) respectively and duplicates the pulmonary hypertension rat model, normal control group disposable celiac injection equivalent saline water, and each treated animal number is 10.With the positive contrast of Virga; The result shows: control group, model group, Virga group (i.g.; 100mg/kg/d, one week of administration in advance before the modeling) and test-compound group (i.g., 100mg/kg/d; One week of administration in advance before the modeling): mPAP is respectively 17.8 ± 2.5mmHg, 35.3 ± 4.6mmHg, 29.8 ± 3.4mmHg and 24.1 ± 2.3mmHg, and test-compound significantly reduces mPAP (P＜0.01) and effect is superior to the Virga group; MRVP is respectively 21.6 ± 2.0mmHg, 35.1 ± 3.3mmHg, 26.8 ± 2.4mmHg and 23.2 ± 2.2mmHg, and test-compound significantly reduces mRVP (P＜0.01) and effect is superior to the Virga group.Normal control group pulmonary artery tube wall is poor, and endotheliocyte is flat, and cell distribution is even continuously, and big or small thickness is relatively more consistent; Right ventricle does not have and thickens, and myocardium of right ventricle cell band is clear, and nuclear is placed in the middle.The model group right ventricle is obviously plump, visible loose myocardial cell, and nuclear is slight to be increased and engrain, and matter is seen inflammatory cell infiltration between flesh; Lung arteriole wall thickening, luminal stenosis, the visible massive inflammatory cells infiltrated of lung tissue is main with lymphocyte.The test-compound group compares myocardial hypertrophy with model group and myocardium oedema alleviates, and lung arteriole tube wall thickens, luminal stenosis alleviates, and the lung tissue inflammatory cell infiltration alleviates.
Embodiment 3
Test-compound [5-((4-(2-diuril azoles also [5,4-d] pyrimidine-7-is amino) piperidines-1-yl) methyl)-2-fluorobenzonitrile list fumarate] is to the preventive and therapeutic effect of Hypoxic Pulmonary Hypertension in Rats:
Rats in normal control group is raised in atmospheric pressure environment, and all the other are respectively organized rat and give and will thickly in administration is placed on the hypobaric hypoxia cabin, raise, and simulation height above sea level 5000m height (about 50kPa) carried out 8 hours every day, continued for 3 weeks, and each treated animal number is 10.With the positive contrast of Virga; The result shows: control group, model group, Virga (i.g.; 100mg/kg/d) group and test-compound group (i.g.; 100mg/kg/d): mPAP is respectively 18.9 ± 2.7mmHg, 37.3 ± 4.2mmHg, 29.3 ± 3.7mmHg and 25.1 ± 2.2mmHg, and test-compound significantly reduces mPAP (P＜0.01) and effect is superior to the Virga group; MRVP is respectively 22.8 ± 2.5mmHg, 36.4 ± 3.4mmHg, 27.4 ± 2.6mmHg and 24.1 ± 2.0mmHg, and test-compound significantly reduces mRVP (P＜0.01) and effect is superior to the Virga group.Normal control group pulmonary artery tube wall is poor, and endotheliocyte is flat, and cell distribution is even continuously, and big or small thickness is relatively more consistent; Right ventricle does not have and thickens, and myocardium of right ventricle cell band is clear, and nuclear is placed in the middle.The model group right ventricle is obviously plump, visible loose myocardial cell, and nuclear is slight to be increased and engrain, and matter is seen inflammatory cell infiltration between flesh; Lung arteriole wall thickening, luminal stenosis, the visible massive inflammatory cells infiltrated of lung tissue is main with lymphocyte.The test-compound group compares myocardial hypertrophy with model group and myocardium oedema alleviates, and lung arteriole tube wall thickens, luminal stenosis alleviates, and the lung tissue inflammatory cell infiltration alleviates.
Should be understood that, concerning those of ordinary skills, can improve or conversion, and all these improvement and conversion all should belong to the protection domain of accompanying claims of the present invention according to above-mentioned explanation.
Claims (4)
1. thiazole and pyrimidine compound, its chemistry 5-by name ((4-(2-diuril azoles also [5,4-d] pyrimidine-7-is amino) piperidines-1-yl) methyl)-2-fluorobenzonitrile list fumarate (1), its structural formula is following:
2. the preparation method of thiazole according to claim 1 and pyrimidine compound is characterized in that synthetic route is following:
Operation steps is: with 4-tertiary butyl carbamate piperidines and 2-fluoro-5-formyl radical benzene nitrile is raw material; Under sodium triacetoxy borohydride and acetic acid effect, synthetic 1-(3-cyanic acid-4-luorobenzyl)-4-tertiary butyl carbamate piperidines adds TFA-DCM then and further reacts; The protection of sloughing amino obtains 5-((4-amino piperidine-1-yl) methyl)-2-fluorobenzonitrile; With product and 2,7-dichloro thiazole also [5,4-d] pyrimidine at p-MeC
6H
4SO
3React under the condition that H exists, generate 5-((4-(2-diuril azoles also [5,4-d] pyrimidine-7-is amino) piperidines-1-yl) methyl)-2-fluorobenzonitrile, obtain single fumarate with the fumaric acid reaction then.
3. the application of thiazole according to claim 1 and pyrimidine compound is characterized in that: the application in making treatment pulmonary hypertension medicine.
4. the application of thiazole according to claim 3 and pyrimidine compound is characterized in that: said pulmonary hypertension is a Hypoxic Pulmonary Hypertension in Rats.
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| NO941135L (en) * | 1993-04-01 | 1994-10-03 | Daiichi Seiyaku Co | Thiazole pyrimidine derivatives |
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