CN106265673B - A kind of application of compound - Google Patents
A kind of application of compound Download PDFInfo
- Publication number
- CN106265673B CN106265673B CN201610830279.5A CN201610830279A CN106265673B CN 106265673 B CN106265673 B CN 106265673B CN 201610830279 A CN201610830279 A CN 201610830279A CN 106265673 B CN106265673 B CN 106265673B
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- China
- Prior art keywords
- pulmonary hypertension
- drug
- aminopurine
- treatment
- present
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- 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, application of its structural formula (I) compound represented of 2-aminopurine (2-Aminopurine, 2-AP) in treatment pulmonary hypertension.The 2-aminopurine can be used as the drug of sole active agent preparation treatment pulmonary hypertension.The present invention has found that 2-aminopurine inhibits the effect of pulmonary hypertension by experimental study, is especially suitable for pulmonary hypertension caused by treatment hypoxemia.New breakthrough is made that on the pathogenic molecular mechanism research of 2-aminopurine and pulmonary hypertension, provides theoretical foundation and target to prevent and treat new medicament screen and the clinical treatment of condary pulmonary hypertension.
Description
Technical field
The present invention relates to be related to a kind of application of compound.
Background technique
Pulmonary hypertension (pulmonary arterial hypertension, PAH) cause of disease is complicated, by a variety of hearts, lung or
Pulmonary vascular disease causes.With lung parteriole vascular remodeling, the pathological characters of pulmonary arterial vascular smooth muscle proliferation.Show as pulmonary circulation
Pressure and resistance increase, and may occur in which that right cardiac load increases, right heart insufficiency, a series of lung Oligemia, so as to cause clinics
It shows, pulmonary hypertension is often in carry out sexual development in the course of disease.What enhancing pulmonary arterial vascular tension led to right heart failure seriously threatens people
The disease of class life and health.Especially idiopathic arterial PAH patient can just make a definite diagnosis for 2 years or so mostly after there is symptom, and true
Natural history after examining is in 2.5-3.4.It is " primary " and " secondary " two class that PAH, which is divided to, is recognized with to pulmonary hypertension
Gradually deeply, 2003 the World Health Organization (WHO) " pulmonary hypertension meeting " according to the cause of disease, pathologic, physiologic, therapeutic scheme
And Prognostic Characteristics classify to pulmonary hypertension, American Thoracic doctor institutes (ACCP) in 2004 and European cardiovascular disease association
(ESC) this is revised, which has directive significance to the treatment of patients with pulmonary hypertension.
Traditional treatment method includes oxygen uptake, heart tonifying, diuresis, calcium channel blocker and anti-coagulants auxiliary therapeutical agent etc., master
Play the relaxation effect of symptom.It (mainly includes prostacyclin drug that the R&D and promotion of target therapeutic agent in recent years, which uses,
Class, phosphodiesterase 5 inhibitor, endothelin-receptor antagonists and the soluble guanylate cyclase agonist explored recently,
Serotonin transports sub- inhibitor, growth factor receptor inhibitors, Rho kinase inhibitor etc.) and the treatment methods such as living body lung transplantation
Substantially improve the prognosis of patient.These drugs can a degree of symptom for alleviating PAH, in the case for the treatment of patients in
Position life span is only 2.7 years, and pulmonary hypertension still lacks the cure method of special efficacy at present, therefore, finds new specificity and controls
Treating drug is particularly important.
Summary of the invention
In order to solve the problems in the existing technology, it the purpose of the present invention is to provide a kind of therapeutic effect is definite, controls
Treat sitaxsentan sodium object at low cost.
In order to achieve the object of the present invention, technical scheme is as follows:
In a first aspect, the application the present invention provides 2-aminopurine in preparation treatment pulmonary hypertension drug, with 2-
Adenine phosphate prepares the drug for the treatment of pulmonary hypertension as active constituent.
Further, the medicine of application preparation treatment pulmonary hypertension using 2-aminopurine as sole active agent
Object.
Further, the 2-aminopurine its be structural formula (I) compound represented:
It should be noted that the compound 2-aminopurine can be bought or be utilized marketable material by commercial sources,
Pass through compound synthesis method synthesis traditional in the prior art.Column chromatography, high performance liquid chromatography can be passed through after synthesis
Or the modes such as crystallization are further purified.
Preferably, the drug is oral preparation.The present invention it is found through experiment that, by the 2-aminopurine structural formula
(I) rat of pulmonary hypertension is suffered from the oral stomach-filling of drug of compound represented preparation, has apparent therapeutic effect.
The present invention pass through experimental studies have found that, 2-aminopurine of the present invention and above compound lure hypoxemia and drug
Pulmonary hypertension animal model caused by leading has apparent therapeutic effect.
But it should be recognized that pulmonary hypertension of the present invention covers pulmonary artery caused by known a variety of pathogenesis
High pressure, such as arteriosity pulmonary hypertension (PAH) (including caused by idiopathic, hereditability, drug and poisonous substance and newborn's duration), left
The disease associated pulmonary hypertension of the heart (including cardiac systolic function is not complete, Diastolic Heart failure and valvular heart disease), pulmonary disease or
Pulmonary hypertension caused by hypoxemia (including Chronic Obstructive Pulmonary Disease, Interstitial Lung Disease, sleep apnea syndrome,
Chronic plateau sickness), pulmonary hypertension caused by chronic thromboembolic pulmonary hypertension and other unknown factors, wherein for
Pulmonary hypertension application effect caused by hypoxemia is more significant.
The dosage form of described pharmaceutical composition can be any pharmaceutical dosage form, these dosage forms include: tablet, sugar-coat
Tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral solution, mouth containing agent, granule, punching
Agent, powder, paste, sublimed preparation, suspension, pulvis, solution, injection, suppository, ointment, emplastrum, creme, is sprayed pill
Agent, drops, patch;It is preferred that peroral dosage form, such as: capsule, tablet, oral solution, granule, pill, powder, sublimed preparation, paste.
The peroral dosage form can contain common excipient, such as adhesive, filler, diluent, tablet agent, lubricant, disintegration
Agent, colorant, flavoring agent and wetting agent when necessary can be coated tablet.Suitable filler includes cellulose, mannose
Alcohol, lactose and other similar fillers;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/day, it is proposed that used in human body described pharmaceutical composition preferred effective dose between 0.15~15mg/kg body weight/day
Between;Between more preferably 1.5~8mg/Kg body weight/day." the treatment effective dose " can be used for the single of related disease
Medication or drug combination treatment.
It is described treatment pulmonary hypertension pharmaceutical composition (medicament) it is preferable to use method be it is oral, preferred dosage is every
Its 10~50mg/Kg, daily regular time stomach-filling processing are primary.
The beneficial effects of the present invention are:
The present invention has found that 2-aminopurine inhibits the effect of pulmonary hypertension by experimental study, in 2-aminopurine and
New breakthrough is made that on the pathogenic molecular mechanism research of pulmonary hypertension, for the new drug sieve for preventing and treating condary pulmonary hypertension
Choosing and clinical treatment provide theoretical foundation and target.
The present invention further determined that structural formula (I) compound represented in 2-aminopurine controls pulmonary hypertension
Treatment effect is especially suitable for pulmonary hypertension caused by treatment hypoxemia.
Technical solution provided by the invention has stronger clinical meaning, can be pulmonary hypertension precautionary measures and treatment side
Method optimization provides solid foundation.
Specific embodiment
2-aminopurine (2-Aminopurine, 2-AP) is purchased from Sigma Co., USA.
The preferred embodiment of the present invention is described in detail below in conjunction with embodiment.It will be appreciated that following real
Providing merely to play the purpose of explanation for example is applied, is not used to limit the scope of the present invention.The skill of this field
Art personnel without departing from the spirit and purpose of the present invention, can carry out various modifications and replace to the present invention.
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
Detailed description of the invention
Fig. 1 is that 2-aminopurine is handled to hypoxia inducible rat pulmonary hemodynamics and right ventricle in the embodiment of the present invention 1
The influence result of plump degree;
Fig. 2 is the influence that 2-aminopurine handles to hypoxia inducible rat right ventricular accounting in the example 1 of the invention implemented
As a result;
Fig. 3 is that 2-aminopurine is handled to the shadow to hypoxia inducible rat artery middle layer wall ratio in the embodiment of the present invention 1
Loud result;
Fig. 4 is that 2-aminopurine is handled to hypoxia inducible rat tube wall middle layer cross-sectional area ratio in the embodiment of the present invention 1
The result of influence.
Influence test of the embodiment 2-aminopurine to pulmonary hypertension caused by hypoxemia
Male Sprague Dawley (SD) rat purchased from Beijing tie up experimental animal Co., Ltd, tonneau China, weight 200 ±
20g is randomly divided into 5 groups (every group 10) (normal diet is purchased from Jun Ke institute, and mouse is freely eaten).First group of normal oxygen control
Group, second group of anoxia model control group, third group anoxia model dissolution control, 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 in the normal oxygen (21%O of normal pressure2) ring
Border raising, remaining each group are placed in normal pressure low oxygen cabin (oxygen concentration 11%O2) continuous hypoxemia is carried out, continue 6 weeks.2- amino
Purine treatment group (the 4th group and the 5th group) is after modeling starts 2 weeks, and daily gastric infusion 1 time is for 4 weeks.Normal oxygen control
Group and model control group (second group and third group) are after modeling starts 2 weeks, and the solvent of equivalent is given in stomach-filling before each anoxic
As control.
1, hemodynamic index measures: filled with heparin solution, (0.9% sodium chloride is molten for vena jugularis externa insertion on the right side of from rat
Liquid+heparin 10U/m1) vinyon microtubular, the other end of conduit be connected with micro pressure sensor monitoring pressure become
Change, under the guidance of pressure waveform, conduit enters right room, tricuspid orifice, right ventricle (RV) through superior vena cava, finally enters pulmonary artery
It is dry, measure mean pulmonary arterial pressure (mPAP) and right ventricular systolic end pressure (RVSP) etc..After stablizing 30 minutes, POWERLAB is used
The acquisition of multiple tracks intelligence Physiological Signal Acquiring System, record and analysis indices.
2, it the measurement of the plump index of right ventricle (RV): after experiment, cuts open chest and takes out mouse heart, cut off atrial tissue.
Go out RV, left ventricle (LV) and interventricular septum (S) along interventricular septum edge separation, with the weight for weighing RV, LV and S after filter paper suck dry moisture
Amount reflects RV plumpness degree (Fig. 2) with RV/ (LV+S) ratio.
3, Pulmonary Vascular pathological examination: taking tissue block from inferior lobe of right lung same area, is placed in 10% neutral formalin (pH7.4)
Fix 2 days.Routine paraffin wax embedding, serial section, hematoxylin eosin staining and elastic fibers dye (Hart improved method Dyeing shell
Power fiber, Van Gieson are redyed), light microscopic observation lung parteriole morphological change.And it is fine with image analyzer measurement elastic force
The outer diameter (ED) for the lung parteriole (diameter is less than 100 μm) gone in dimension stained slice with respiratory bronchiole and breathing companion,
Arterial media wall thickness (MT), tube wall middle layer cross-sectional area (MA), vessel lumen cross-sectional area (VA) and blood vessel total cross-sectional area
(TAA), the percentage (MT%) (Fig. 3) that vascular wall intima-media thickness accounts for outer diameter, vascular wall middle layer cross-sectional area are then calculated separately
The percentage (MA%) (Fig. 4) of blood vessel total cross-sectional area is accounted for, reflects lung thin vessels tube wall thickening degree.Every rat lung sections are total
The These parameters for measuring 6~10 lung parterioles, calculate blood vessel index parallel statistical analysis of the mean as this rat.
The influence of each group Pulmonary Vessels in Rats pathological index and right ventricle plumpness
According to the test result (* P < 0.05, * * P < 0.01) of figure -4 as can be seen that Normal group right ventricle is without increasing
Thickness, anoxic control group right ventricle is obviously plump, and right ventricle plumpness index RV/ (LV+S) is significantly raised.Pathological examination discovery: anoxic
The cardiac muscle cell of the visible hypertrophy of control group right ventricle, pulmonary artery thicken, luminal stenosis.And two dosage groups of 2-aminopurine
All have improvement result to the remodeling of the pathology of pulmonary artery, including reduce arterial media wall ratio, tube wall middle layer cross-sectional area ratio and
Right ventricular hypertrophy is reduced, and has certain dose dependent.
Claims (7)
1.2- adenine phosphate preparation treatment pulmonary hypertension drug in application, which is characterized in that using 2-aminopurine as
The drug of active constituent preparation treatment pulmonary hypertension, it is structural formula (I) compound represented to the 2-aminopurine,
2. application according to claim 1, which is characterized in that prepare treatment using 2-aminopurine as sole active agent
The drug of pulmonary hypertension.
3. according to claim 1 to 2 described in any item applications, which is characterized in that the effective dose of the drug be 0.1~
200mg/kg rat body weight/day;The effective dose of affiliated drug is 0.15~15mg/kg body weight/day.
4. described in any item applications according to claim 1~2, which is characterized in that the drug is oral preparation.
5. described in any item applications according to claim 1~2, which is characterized in that the pulmonary hypertension be low-oxygen environment and
Pulmonary hypertension caused by drug-induced.
6. application according to claims 1 to 2, which is characterized in that the drug is powder, tablet, granule, capsule
Agent, suspension, emulsion or injection.
7. described in any item applications according to claim 1~2, which is characterized in that the drug is changed as shown in structural formula (I)
Available auxiliary material in object and pharmacy is closed to be prepared.
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CN201610830279.5A CN106265673B (en) | 2016-09-18 | 2016-09-18 | A kind of application of compound |
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CN201610830279.5A CN106265673B (en) | 2016-09-18 | 2016-09-18 | A kind of application of compound |
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CN106265673B true CN106265673B (en) | 2019-09-20 |
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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 |
---|
Hypoxia-inducible factor 1 and the molecular physiology of oxygen homeostasis;GREGG L. SEMENZA;《J Lab Clin Med》;19980331;第131卷(第3期);第207-214页 * |
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