CN106265673A - A kind of application of compound - Google Patents
A kind of application of compound Download PDFInfo
- Publication number
- CN106265673A CN106265673A CN201610830279.5A CN201610830279A CN106265673A CN 106265673 A CN106265673 A CN 106265673A CN 201610830279 A CN201610830279 A CN 201610830279A CN 106265673 A CN106265673 A CN 106265673A
- Authority
- CN
- China
- Prior art keywords
- pulmonary hypertension
- medicine
- application
- aminopurine
- amidopurin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
Abstract
The present invention relates to compound, the application in treatment pulmonary hypertension of 2 amidopurin (2 Aminopurine, 2 AP) its compound shown in structure formula I.Described 2 amidopurin can be as the medicine of sole active agent preparation treatment pulmonary hypertension.The present invention is found that the effect of 2 amidopurin suppression pulmonary hypertensions by experimental study, is especially suitable for treatment pulmonary hypertension caused by hypoxemia.Being made that new breakthrough on the molecular mechanism research caused a disease of 2 amidopurin and pulmonary hypertension, new medicament screen and clinical treatment for preventing and treating condary pulmonary hypertension provide theoretical foundation and target.
Description
Technical field
The present invention relates to relate to the application of a kind of compound.
Background technology
Pulmonary hypertension (pulmonary arterial hypertension, the PAH) cause of disease is complicated, by the multiple heart, lung or
Pulmonary vascular disease causes.With lung small artery vascular remodeling, the pathological characters of pulmonary artery smooth muscle proliferation.Show as pulmonary circulation
Pressure and resistance increase, and may occur in which that right cardiac load increases, right heart insufficiency, lung Oligemia, thus cause a series of clinic
Performance, in the course of disease, pulmonary hypertension often develops in Progressive symmetric erythrokeratodermia.Strengthen pulmonary artery tension force and cause the serious threat people of right heart failure
The disease of class life and health.Particularly idiopathic arterial PAH patient just can make a definite diagnosis for many about 2 years after there is symptom, and true
Natural history after examining is at 2.5-3.4.PAH is divided into " constitutional " and " Secondary cases " two class, along with recognizing pulmonary hypertension
Progressively deeply, 2003 World Health Organization (WHO) (WHO) " pulmonary hypertension meeting " according to the cause of disease, Pathophysiology, therapeutic scheme
And pulmonary hypertension classified by Prognostic Characteristics, American Thoracic doctor institute (ACCP) in 2004 and Europe cardiovascular diseases association
(ESC) being revised this, this sorting technique has directive significance to the treatment of patients with pulmonary hypertension.
Traditional Therapeutic Method includes oxygen uptake, heart tonifying, diuresis, calcium channel blocker and anticoagulant auxiliary therapeutical agent etc., main
The mitigation of symptom to be played.The R&D and promotion of target therapeutic agent in recent years uses and (mainly includes prostacyclin medicine
Class, phosphodiesterase 5 inhibitor, endothelin-receptor antagonists and the sGC agonist recently explored,
5-hydroxy tryptamine transhipment sub-inhibitor, growth factor receptor inhibitors, Rho inhibitors of kinases etc.) and the Therapeutic Method such as live body lung transplantation
Substantially improve the prognosis of patient.These medicines can the symptom of a certain degree of alleviation PAH, in the case for the treatment of patients in
Position life span is only 2.7 years, and current pulmonary hypertension still lacks the cure method of specially good effect, therefore, finds new specificity and controls
Treatment medicine is particularly important.
Summary of the invention
In order to solve problems of the prior art, it is an object of the invention to provide a kind of therapeutic effect definite, control
Treat the sitaxsentan sodium thing of low cost.
In order to realize the object of the invention, technical scheme is as follows:
First aspect, the invention provides 2-aminopurine application in preparation treatment pulmonary hypertension medicine, with 2-
Amidopurin is as the medicine of active component preparation treatment pulmonary hypertension.
Further, described application is using 2-aminopurine as the medicine of sole active agent preparation treatment pulmonary hypertension
Thing.
Further, described 2-aminopurine at least includes the compound shown in structure formula I:
It should be noted that described compound 2-aminopurine can be bought by commercial sources or utilize marketable material,
Synthesized by compou nd synthesis method traditional in prior art.Column chromatography, high performance liquid chromatography can be passed through after synthesis
Or the mode such as crystallization is further purified.
As preferably, described medicine is oral formulations.The present invention finds through test, by described 2-aminopurine structural formula
(I) medicine per os gavage prepared by the compound shown in suffers from the rat of pulmonary hypertension, has obvious therapeutic effect.
The present invention is by experimental studies have found that, hypoxia and medicine are lured by 2-aminopurine of the present invention with above-claimed cpd
Lead caused pulmonary hypertension animal model and have obvious therapeutical effect.
But it should be recognized that pulmonary hypertension of the present invention contains the pulmonary artery that known multiple pathogenesis causes
High pressure, such as arterialness pulmonary hypertension (including caused by idiopathic, hereditability, medicine and poisonous substance and neonate persistence), left
The disease associated pulmonary hypertension of the heart (include that cardiac systolic function is complete, Diastolic Heart failure and valvular heart disease), pulmonary disease or
Pulmonary hypertension caused by hypoxemia (include chronic obstructive pulmonary disease, Interstitial Lung Disease, sleep apnea syndrome,
Chronic plateau sickness), chronic thromboembolic pulmonary hypertension, and pulmonary hypertension caused by other not clear factors, wherein, for
Pulmonary hypertension application effect caused by hypoxemia is the most notable.
The dosage form of described pharmaceutical composition can be any pharmaceutically useful dosage form, and these dosage forms include: tablet, sugar-coat
Tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, punching
Agent, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, ointment, plaster, cream, spraying
Agent, drop, patch；Preferred oral dosage form, such as: capsule, tablet, oral liquid, granule, pill, powder, sublimed preparation, unguentum etc..
Described peroral dosage form can be containing conventional excipient, such as binding agent, filler, diluent, tablet agent, lubricant, disintegrate
Agent, coloring agent, flavoring agent and wetting agent, can be coated tablet if desired.Suitable filler includes cellulose, mannose
The filler that alcohol, lactose are similar with other；Suitable disintegrating agent includes starch, polyvinylpyrrolidone and starch derivatives, example
Such as sodium starch glycollate；Suitable lubricant includes, such as magnesium stearate.Suitable pharmaceutically acceptable wetting agent includes ten
Sodium dialkyl sulfate.
The treatment effective dose of pharmaceutical composition of the present invention is between 0.1～200mg/kg body weight/day.The present invention
The preferred effective dose of described pharmaceutical composition is between 1～100mg/kg body weight/day；More preferably l0～50mg/Kg body
Between weight/sky, it is proposed that be used in the preferred effective dose of described pharmaceutical composition of human body between 0.15～15mg/kg body weight/day
Between；Between more preferably 1.5～8mg/Kg body weight/day.Described " treatment effective dose " can be used for the single of relevant disease
Medication or drug combination treatment.
Pharmaceutical composition (medicament) method of being preferably used of described treatment pulmonary hypertension is oral, and preferred dosage is every
It 10～50mg/Kg, regular time every day gavage process once.
The beneficial effects of the present invention is:
The present invention is found that the effect of 2-aminopurine suppression pulmonary hypertension by experimental study, at 2-aminopurine and
It is made that new breakthrough, for the new drug sieve of preventing and treating condary pulmonary hypertension on the molecular mechanism research caused a disease of pulmonary hypertension
Choosing and clinical treatment provide theoretical foundation and target.
The present invention further determined that pulmonary hypertension is controlled by the compound shown in structure formula I in 2-aminopurine
Treatment effect, is especially suitable for treatment pulmonary hypertension caused by hypoxemia.
The technical scheme that the present invention provides has stronger clinical meaning, can be pulmonary hypertension preventive measure and treatment side
Method optimization provides solid foundation.
Detailed description of the invention
2-aminopurine (2-Aminopurine, 2-AP), purchased from Sigma Co., USA.
Below in conjunction with embodiment, the preferred embodiment of the present invention is described in detail.It will be appreciated that following reality
Execute providing merely to play descriptive purpose of example, be not used to the scope of the present invention is limited.The skill of this area
Art personnel, in the case of without departing substantially from spirit of the invention and spirit, can carry out various amendment and replacement to the present invention.
Experimental technique used in following embodiment if no special instructions, is conventional method.
Material used in following embodiment, reagent etc., if no special instructions, the most commercially obtain.
Accompanying drawing explanation
Fig. 1 is that in the embodiment of the present invention 1,2-aminopurine processes hypoxia inducible induced lung hemodynamics and right ventricle
Plumpness degree affect result；
Fig. 2 is the impact that in the example 1 that the present invention implements, 2-aminopurine processes on hypoxia inducible rat right ventricular accounting
Result；
Fig. 3 is that in the embodiment of the present invention 1,2-aminopurine processes the shadow to hypoxia inducible rat artery middle level wall ratio
The result rung；
Fig. 4 is that in the embodiment of the present invention 1,2-aminopurine processes hypoxia inducible rat tube wall middle level cross-sectional area ratio
The result of impact.
The impact of pulmonary hypertension caused by hypoxia is tested by embodiment 2-aminopurine
Male Sprague Dawley (SD) rat purchased from Beijing dimension tonneau China laboratory animal company limited, body weight 200 ±
20g, is randomly divided into 5 groups (often group 10) (normal diet is purchased from Jun Ke institute, mice free choice feeding).First group of normal oxygen comparison
Group, second group of anoxia model matched group, the 3rd group of anoxia model dissolve comparison, the 4th group of 2-aminopurine low dose group (10mg/
Kg/d), the 5th group of 2-aminopurine high dose group (50mg/kg/d).Rats in normal control group is at normal pressure normal oxygen (21%O2) ring
Border is raised, and remaining each group is placed in (oxygen concentration 11%O in normal pressure low oxygen cabin2) carry out continuous hypoxia, continue 6 weeks.2-amino
Purine treatment group (the 4th group and the 5th group) is after modeling starts 2 weeks, and every day, gastric infusion 1 time, continued 4 weeks.Normal oxygen comparison
Group and model control group (second group and the 3rd group) are after modeling starts 2 weeks, and before each anoxia, gavage gives the solvent of equivalent
As comparison.
1, hemodynamic index measures: on the right side of rat, external jugular vein inserts and is filled with heparin solution (0.9% sodium chloride is molten
Liquid+heparin 10U/m1) vinyon microtubular, the other end of conduit be connected with micro pressure sensor monitoring pressure become
Changing, under the guiding of pressure waveform, conduit enters right room, tricuspid orifice, right ventricle (RV) through superior vena cava, finally enters pulmonary artery
Dry, measure mean pulmonary arterial pressure (mPAP) and right ventricular systolic end pressure (RVSP) etc..After stablizing 30 minutes, use POWERLAB
Multiple tracks intelligence Physiological Signal Acquiring System collection, record and analyze indices.
2, the mensuration of the plump index of right ventricle (RV): after experiment terminates, cut open breast and take out mouse heart, cut off atrial tissue.
RV, left ventricle (LV) and interventricular septum (S) is gone out, with the weight weighing RV, LV and S after filter paper suck dry moisture along interventricular septum edge separation
Amount, reflects RV plumpness degree (Fig. 2) with RV/ (LV+S) ratio.
3, Pulmonary Vascular pathology detection: take piece of tissue from inferior lobe of right lung same area, is placed in 10% neutral formalin (pH7.4)
Fix 2 days.Routine paraffin wax embeds, serial section, hematoxylin-eosin staining and elastic fibers dyeing (Hart improved method Dyeing shell
Power fiber, Van Gieson redyes), light Microscopic observation lung small artery morphological change.And it is fine to measure elastic force with image analyzer
Dimension stained is accompanied with respiratory bronchioles and alveolar duct the lung small artery (diameter is less than 100 μm) of row external diameter (ED),
Arterial media wall thickness (MT), tube wall middle level cross-sectional area (MA), vessel lumen cross-sectional area (VA) and the total cross-sectional area of blood vessel
(TAA), calculate blood vessel wall intima-media thickness the most respectively and account for the percentage ratio (MT%) (Fig. 3) of external diameter, blood vessel wall middle level cross-sectional area
Account for the percentage ratio (MA%) (Fig. 4) of the total cross-sectional area of blood vessel, reflect lung thin vessels tube wall thickening degree.Every induced lung section is altogether
Measure the These parameters of 6～10 lung small artery, calculate the mean parallel statistical analysis of blood vessel index as this rat.
Each group Pulmonary Vessels in Rats pathological index and the impact of right ventricle plumpness
Result of the test (* P ＜ 0.05, * * P ＜ 0.01) according to figure-4 is it can be seen that Normal group right ventricle is without increasing
Thickness, anoxia matched group right ventricle is the most plump, and right ventricle plumpness index RV/ (LV+S) is significantly raised.Pathology detection finds: anoxia
Myocardial cell loose seen from matched group right ventricle, pulmonary artery thickens, luminal stenosis.And two dosage groups of 2-aminopurine
All Pulmonic pathology has been reinvented improvement result, including reduce arterial media wall ratio, tube wall middle level cross-sectional area ratio and
Reduce right ventricular hypertrophy, and have certain dose dependent.
Claims (9)
1.2-amidopurin preparation treatment pulmonary hypertension medicine in application, it is characterised in that using 2-aminopurine as
The medicine of active component preparation treatment pulmonary hypertension.
Application the most according to claim 1, it is characterised in that using 2-aminopurine as sole active agent preparation treatment
The medicine of pulmonary hypertension.
Application the most according to claim 1 and 2, it is characterised in that described 2-aminopurine at least includes structure formula I institute
The compound shown
4. the application in preparation treatment pulmonary hypertension medicine of the compound A shown in structure formula I.
5. according to the application described in any one of Claims 1 to 4, it is characterised in that described medicine is oral formulations.
6. according to the application described in any one of Claims 1 to 4, it is characterised in that described pulmonary hypertension be low-oxygen environment and
The drug-induced pulmonary hypertension caused.
Application the most according to claim 6, it is characterised in that described medicine is powder, tablet, granule, capsule, molten
Liquor, Emulsion, suspensoid, Emulsion, effervescent tablet or injection.
Application the most according to claim 7, it is characterised in that described medicine is by the compound shown in structure formula I and medicine
The upper available adjuvant of agent is prepared from.
9. according to the application described in any one of claim 1 to 8, it is characterised in that the effective dose of described medicine be 0.1～
200mg/kg rat body weight/sky；The effective dose of affiliated medicine is 0.15～15mg/kg body weight/sky.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610830279.5A CN106265673B (en) | 2016-09-18 | 2016-09-18 | A kind of application of compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610830279.5A CN106265673B (en) | 2016-09-18 | 2016-09-18 | A kind of application of compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106265673A true CN106265673A (en) | 2017-01-04 |
| CN106265673B CN106265673B (en) | 2019-09-20 |
Family
ID=57712317
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610830279.5A Expired - Fee Related CN106265673B (en) | 2016-09-18 | 2016-09-18 | A kind of application of compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106265673B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102083437A (en) * | 2008-03-07 | 2011-06-01 | 雷·W·埃克斯利 | Treatment of herpes virus related diseases |
| CN103351389A (en) * | 2006-04-26 | 2013-10-16 | 西格诺药品有限公司 | Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith |
-
2016
- 2016-09-18 CN CN201610830279.5A patent/CN106265673B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103351389A (en) * | 2006-04-26 | 2013-10-16 | 西格诺药品有限公司 | Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith |
| CN102083437A (en) * | 2008-03-07 | 2011-06-01 | 雷·W·埃克斯利 | Treatment of herpes virus related diseases |
Non-Patent Citations (1)
| Title |
|---|
| GREGG L. SEMENZA: "Hypoxia-inducible factor 1 and the molecular physiology of oxygen homeostasis", 《J LAB CLIN MED》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106265673B (en) | 2019-09-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100999470B (en) | Salvia minium phenolic acid A and process of preparing preparation and use | |
| CN1899400B (en) | Detection method for injection containing ginseng and aconite root in raw material | |
| WO2004096249A1 (en) | A composition containing radix codonopsis pilosulae and radix astragali and hedysari, method of producing it and use thereof | |
| JP2013528649A (en) | Ranolazine for use for the treatment of pulmonary hypertension | |
| CN109260182B (en) | Application of cannabidiol in preparation of medicine for treating pulmonary hypertension | |
| CN106177960B (en) | Angiotensin receptor antagonist and the compound of enkephalinase inhibitor and application thereof | |
| US11752122B2 (en) | N-acetylcysteine attenuates aortic stenosis progression by inhibiting shear-mediated TGF-beta activation and signaling | |
| CN106265673A (en) | A kind of application of compound | |
| CN103385995B (en) | Traditional Chinese medicine compound for treating arrhythmia and preparation method thereof | |
| CN106344554B (en) | Application of the Resina garciniae extract in treatment pulmonary hypertension | |
| CN106214680B (en) | A kind of compound of angiotensin receptor antagonist and Levosimendan and application thereof | |
| CN109674793A (en) | Benzoylmesaconine, benzoyl aconine, benzoyl time aconine are preparing the application in cardiotonic agents | |
| CN110038002A (en) | Salviandic acid A prevents and treats the purposes of muscular atrophy, myopathy and muscle skeleton complication | |
| CN104398503B (en) | Use of fargesin and its derivative in preparation of drugs for treating or preventing pulmonary hypertension | |
| CN107744571A (en) | A kind of pharmaceutical composition for improving blood vessel endothelium dysfunction and its production and use | |
| CN100339092C (en) | Chinese medicine composition for treating apoplexy and its prepn process and use | |
| CN112516136B (en) | Application of sulbactam sulfate in preparation of heart failure resistant product | |
| WO2021135665A1 (en) | Application of tetrahydrocannabivarin in prevention and/or treatment of pulmonary arterial hypertension | |
| CN101129462A (en) | Method of preparing traditional Chinese medicine composition for treating coronary disease and quality control method thereof | |
| TW201622715A (en) | Method of treating idiopathic pulmonary fibrosis | |
| CN104688836B (en) | A kind of Chinese medicine preparation for treating angiosteosis caused by CKD | |
| CN108159246A (en) | A kind of Chinese medicine composition for preventing Cardiorenal syndrome | |
| CN105622528B (en) | A kind of compound for treating pulmonary hypertension and its application | |
| CN114984087B (en) | Traditional Chinese medicine composition, decoction and pharmaceutical composition, and preparation method and application thereof | |
| CN107998385A (en) | Purposes of the hirudin as prevention antihyperuricemic disease drug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190920 Termination date: 20200918 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |