CN109912600A - It is a kind of prevent and treat pulmonary fibrosis imidazopyrimidine analog derivative and its application - Google Patents
It is a kind of prevent and treat pulmonary fibrosis imidazopyrimidine analog derivative and its application Download PDFInfo
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- CN109912600A CN109912600A CN201910134203.2A CN201910134203A CN109912600A CN 109912600 A CN109912600 A CN 109912600A CN 201910134203 A CN201910134203 A CN 201910134203A CN 109912600 A CN109912600 A CN 109912600A
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- imidazopyrimidine
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- 150000005237 imidazopyrimidines Chemical class 0.000 title claims abstract description 27
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Abstract
The present invention provides a kind of imidazopyrimidine analog derivative for preventing and treating pulmonary fibrosis, the structural formula of the derivative is
Description
Technical field
The invention belongs to drug field, it is related to a kind of imidazopyrimidine analog derivative for preventing and treating pulmonary fibrosis and this spreads out
Application of the biology in the drug of preparation prevention and treatment pulmonary fibrosis.
Background technique
Diffusivity pulmonary interstitial fibrosis (referred to as " pulmonary fibrosis ") is chemically or lung caused by physical equal many reasons
After function progressive, irreversible damage, the result of body reparation generation.Pulmonary fibrosis is broadly divided into idiopathic pulmonary interstitial fiber
Change and secondary pulmonary interstitial fibrosis.Usually on fibroblast proliferation, extrtacellular matrix deposition, interstitial lung inflammation, alveolar
Skin is persistently damaged and alveolar structure disorder is major pathologic features, is clinically mainly shown as expiratory dyspnea, hypoxemia, and
With advancing of disease, the compliance of lungs can reduce, and lung volume is reduced, and lung function is gradually reduced, and patient finally can be because of breathing
Functional failure and it is dead.
In recent years, the trend risen year by year is presented in the patient morbidity of China's pulmonary fibrosis, due to the morbidity of pulmonary fibrosis
Mechanism is unclear, and the effective treatment method of shortage and prognosis are poor, the time limit once patient for being diagnosed as pulmonary embolism is survived
Only 2~3 years.According to research reports, the disease incidence of the pulmonary fibrosis of the country such as the U.S., Canada is also in the trend to go up year by year,
2016 annual datas show that the U.S. increases pulmonary fibrosis patient up to 4.8 ten thousand or so newly every year, and wherein male's disease incidence is higher than women,
Up to 60% patient is dead due to respiratory failure, and the U.S. is used to treat the funds of the disease using up to 2,000,000,000 or so every year, suffers from
Person's poor prognosis, social economy's pressure are big.In China, pulmonary fibrosis, which has become, threatens a big severe of our people's health difficult
Disease equally causes very big economic pressures.
Pulmonary fibrosis pathogenic factor multiplicity, including by genetic predisposition, environment adverse factor, drug-induced pulmonary disease, infection EB
Caused by virus, hepatitis C virus, herpesviral etc., tumor chemoradiotherapy etc. also can lead to pulmonary fibrosis.The diagnosis of this kind of disease compared with
For difficulty, generally requires and carry out chest high-resolution CT examination and bronchoalveolar lavage etc., also need various methods when necessary
Carry out lung bioplsy and pathologic finding.Numerous studies discovery, the pathogenesis of pulmonary fibrosis mainly with inflammatory reaction, oxidative stress and
Epithelial cell damage, fibroblast activation etc. are related.Currently, the method for traditional treatment pulmonary fibrosis is based on hormone, it is clinical
On be often used based on glucocorticoid, immunomodulator, antioxidant etc., but it is bad to be used for a long time clinical effectiveness, and can generate
Some inevitable adverse reactions, also will increase the risks such as respiratory failure, secondary infection.Clinically use Nintedanib more:
1H- Indole-6-carboxylic acid, 2,3- dihydro-3- [[[4- [methyl [(4- methyl-1-piperazinyl) acetyl group] amino] phenyl] amino]
Phenylmethylene] -2- oxygen -, methyl esters, (3Z)-treats idiopathic pulmonary fibrosis, but the common gastrointestinal tract of Nintedanib and liver and gallbladder are bad
Reaction, thereby increases and it is possible to influence fecundity, pregnant woman's disabling, also there are also to be further improved for pharmacokinetics aspect.Many Chinese medicines
Because pulmonary fibrosis pathogenic factors is complicated, and it is often accompanied by the multi viscera lesion centered on lung, the case where simulataneous insufficiency and excessive occurs, facing
It needing to examine etiology and pathogenesis in detail in bed practice, by dialectical main points, accomplishes giving consideration to both the incidental and fundamental, diagnosis and treatment based on an overall analysis of the illness and the patient's condition is integrally-regulated, so as to improve
Patient clinical symptom can prevent to a certain extent and delay pulmonary fibrosis, but in Chinese medicine therapeutic process, the mark of Syndrome Types of TCM
Quasi- and recipe composition there is no unification reliably using standard, to lack Big Clinical Samples and polycentric randomized controlled trial.Institute
With, though there is the appearance of the newer treatment means such as cell factor and its specific inhibitor treatment, gene therapy, Chinese medicine, but still
There is an urgent need to good effect, it is less side effects, can improve patient's prognosis and improve survival rate novel anti-fibrosis drug go out
It is existing.
Summary of the invention
It is an object of the invention to provide a kind of prevention and treatment for defect and deficiency existing for existing pulmonary fibrosis therapeutic agent
Application of the imidazopyrimidine analog derivative and the derivative of pulmonary fibrosis in the drug of preparation prevention and treatment pulmonary fibrosis, with
Solve the problems, such as that toxic side effect existing for existing prevention and treatment pulmonary fibrosis medicine is larger and pharmacokinetics performance is to be improved.
Shown in the structural formula such as formula (I) of the imidazopyrimidine analog derivative of prevention and treatment pulmonary fibrosis provided by the invention, or
The derivative is formula (I) compound represented pharmaceutically acceptable salt,
In the technical solution of the imidazopyrimidine analog derivative of above-mentioned prevention and treatment pulmonary fibrosis, chemical combination shown in the formula (I)
Object pharmaceutically acceptable salt be formula (I) compound represented and hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, succinic acid,
What tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or ferulic acid were formed
Addition salts.
The imidazopyrimidine analog derivative of prevention and treatment pulmonary fibrosis provided by the invention can be with the carrier that pharmaceutically receives, such as target
Common play, which is combined, to nano-carrier etc. prevents and treats pulmonary embolism activity.
The imidazopyrimidine analog derivative of prevention and treatment pulmonary fibrosis provided by the invention can be used drug conventional method and be prepared into
The preparations such as oral, spraying, lozenge, injection.
It is provided by the invention prevention and treatment pulmonary fibrosis imidazopyrimidine analog derivative the preparation method is as follows:
Hypoxanthine, Iso-Propyl iodide and sodium hydride are added in dimethyl sulfoxide (DMSO), are stirred to react 3h at 80 DEG C, it
Acid adding is quenched afterwards, and decompression is spin-dried for, and obtains the hypoxanthine of isopropyl modification；The hypoxanthine and lawesson reagent for taking isopropyl to modify
(Lawesson reagent) is added in toluene, is heated to reflux 3h, and decompression is spin-dried for later, crosses silicagel column to obtain the final product.
The present invention also provides the imidazopyrimidine analog derivatives of above-mentioned prevention and treatment pulmonary fibrosis to prevent and treat pulmonary fibrosis in preparation
Drug in application.The present invention confirms the imidazopyrimidine analog derivative energy of above-mentioned prevention and treatment pulmonary fibrosis by zoopery
Enough substantially reduced pulmonary fibrosis pathological degrees, delay pulmonary fibrosis to be in progress.And imidazopyrimidine analog derivative provided by the invention
More clinical line anti-fibrosis drug Nintedanib possesses more preferably pharmacokinetics and lower toxic side effect.
Compared with prior art, technical solution of the present invention has technical effect beneficial below:
The present invention is experiments prove that the imidazopyrimidine analog derivative of the prevention and treatment pulmonary fibrosis being capable of substantially reduced lung
Fibrillatable pathological degree, delays pulmonary fibrosis to be in progress, and has the function of significantly preventing and treating pulmonary fibrosis.Also, it is provided by the invention
The more clinical line anti-fibrosis drug Nintedanib of imidazopyrimidine analog derivative possesses more preferably pharmacokinetics and lower
Toxicity.Reach within about 2-4 hours maximal plasma concentration, the Absolute oral of 100mg dosage after the administration of Nintedanib capsule oral
Availability is 4.69%, and Cpss is reached at least upon administration 1 week, and end-stage half-life period is 10 to 15 hours.Experiment
It can reach maximum plasma concentration, and 50mg dosage in 0.5 hour after confirming imidazopyrimidine analog derivative administration of the invention
Absolute bioavailability be 54.51%, when successive administration, reach steady state plasma concentration two days later, end-stage half-life period is 72 small
When more than, while toxotest show invention provide imidazopyrimidine analog derivative have no obvious adverse reaction.In addition, this hair
The synthesis technology of the imidazopyrimidine analog derivative of the prevention and treatment pulmonary fibrosis of bright offer is simple, can reduce production cost, have warp
The high advantage of Ji property.
Detailed description of the invention
Fig. 1 is blank control group in embodiment 2, model group, treatment group and prevention group mouse lung tissue slice HE dyeing knot
Fruit.
Specific embodiment
Imidazopyrimidine analog derivative to prevention and treatment pulmonary fibrosis provided by the invention and its application by the following examples
It is described further.It is necessary to note that following embodiment is served only for, the invention will be further described, should not be understood as to this hair
The limitation of bright protection scope, one of ordinary skill in the art make some nonessential change according to foregoing invention content, to the present invention
It is embodied into adjustment, still falls within the range of invention protection.
Embodiment 1
In the present embodiment, the imidazopyrimidine analog derivative of preparation prevention and treatment pulmonary fibrosis, steps are as follows:
Hypoxanthine 1.36g, Iso-Propyl iodide 3mL (1.703g/mL) and sodium hydride 0.24g are taken, addition fills 300mL
In the flask of DMSO, it is stirred to react 3h at 80 DEG C, acid adding is quenched later, and decompression is spin-dried for, and obtains the hypoxanthine of isopropyl modification.
Hypoxanthine 1.5g, lawesson reagent (Lawesson reagent) 8.08g for taking isopropyl to modify, addition fill 500mL toluene
Flask in, be heated to reflux 3h, later decompression be spin-dried for, cross silicagel column up to prevent and treat pulmonary fibrosis imidazopyrimidine analog derivative
CSA。
Nucleus magnetic hydrogen spectrum and nuclear-magnetism carbon spectrum detection are carried out to CSA, as a result are as follows:1H NMR(500MHz,Chloroform-d)δ
8.57 (s, 1H), 7.76 (s, 1H), 5.26 (hept, J=6.2Hz, 1H), 4.86 (hept, J=6.2Hz, 1H), 1.46 (d, J
=6.1Hz, 6H), 1.23 (d, J=6.2Hz, 6H).13C NMR(125MHz,Common NMR Solvents)δ178.12,
150.12,142.21,139.31,129.43,53.98,47.79,23.32,21.98,21.13。
Embodiment 2
In the present embodiment, the anti-pulmonary embolism activity of CSA prepared by testing example 1.
1. test method
(1) animal: SPF grades of c57bl/6 mouse, 25g ± 2g.
(2) it is grouped
By animal packet be blank control group, model control group, prevention group and treatment group, every group 10.
Prevention group shifts to an earlier date 14d and carries out pharmaceutical intervention, dosage 50mg/kg/d.It is administered and intervenes after treatment group's modeling, dosage is
50mg/kg/d。
(3) with 1% yellow Jackets with the dosage intraperitoneal injection of mice of 50mg/kg, anesthesia lies on the back and is fixed on operation
Platform is slowly injected 5mg/kg bleomycin, then holds up mouse plate rapidly, rotated 5min with tweezers exposure tracheae (pulling out tongue),
Drug is set to be evenly distributed in intrapulmonary.
Isometric isotonic saline solution is given in blank control group stomach-filling, treatment group start after 10 days with the dosage of 50mg/kg/d into
Row gastric infusion, blank control group and the isometric isotonic saline solution of model control group stomach-filling, prevention group press always 50mg/kg/d's
Dosage carries out gastric infusion, and successive administration was to 35 days, 1 time a day.
(4) materials and index determining
It takes blood to put to death mouse after administration 35 days, collects two lung tissues, weighing takes the same position of superior lobe of right lung, with 4%
Paraformaldehyde fixes 48h, paraffin section, and HE is dyed for pathological study.The same position of left lobi medius pulmonis is taken to carry out lung tissue
The detection of HYP content.Blood plasma is collected, T-SOD, MDA and GSH-PX are detected.
2. result
(1) mouse lung tissue HYP content analysis
The results are shown in Table 1 for each group mouse lung tissue HYP content detection, mouse lung tissue HYP content and blank control group
It compares, each group mouse lung tissue HYP content rises (P < 0.01)；Compared with model control group, pharmaceutical intervention group HYP content is obvious
Decline (P < 0.01).
1 mouse lung tissue HYP content (± s) of table
| Group | HYP(μg/g) |
| Blank control group | 12.3±0.5 |
| Model control group | 92.3±6.2* |
| Prevention group | 24.1±2.2# |
| Treatment group | 31.4±4.1# |
Note: compared with blank control group: P < 0.01 *；Compared with model control group: #P < 0.01.
(2) mice plasma T-SOD, MDA, GSH-PX content analysis
Each group mice plasma T-SOD, MDA, GSH-PX content is compared with blank control group, each group mice plasma MDA content
Rise (P < 0.01)；Compared with blank control group, each group mice plasma T-SOD, GSH-PX content declines (P < 0.01).With model
Control group is compared, and each group mice plasma MDA content is decreased obviously (P < 0.01)；Compared with model control group, each group mice plasma
T-SOD, GSH-PX rise (P < 0.01).
2 mice plasma T-SOD, MDA, GSH-PX content (± s) of table
| Group | T-SOD(U/mL) | MDA(nmol/mL) | GSH-PX(U/L) |
| Blank control group | 192.1±12.5 | 3.6±0.9 | 1121.5±122.5 |
| Model control group | 82.3±9.5 | 25.7±3.5 | 320.5±23.2 |
| Prevention group | 177.1±10.1 | 5.2±1.2 | 991.7±12.3 |
| Treatment group | 159.5±19.4 | 8.7±2.1 | 890.5±23.2 |
Note: compared with blank control group: P < 0.01 *；Compared with model control group: #P < 0.01.
(3) pathologic mutation analysis
Blank control group, model control group, treatment group and prevention group mouse lung tissue are sliced HE coloration result such as Fig. 1 institute
Showing, blank control group lung structure is clear as shown in Figure 1, and model control group alveolar septum significantly broadens, and alveolar structure destroys seriously,
Atrophy collapses seriously, and collagenous fibres significantly increase, and a large amount of inflammatory cell infiltrations occurs, and the pulmonary fibrosis of prevention group and treatment group
It is significant to mitigate.
Embodiment 3
The present embodiment carries out toxotest to CSA.
C57 mouse Compound CSA is given with the dosage stomach-filling of 50mg/kg/d, successive administration 180 days, blank control group filled
Stomach gives isometric isotonic saline solution.After last time administration 1h, mouse peritoneal injects yellow Jackets (40mg/kg) anesthesia, will
It is placed on 37 ± 1 DEG C of constant temperature hot plate, heart puncturing extracting blood.Blood routine, liver kidney function are carried out according to by instrumentation specification
The measurement of the blood pathologic index such as energy, electrolyte, the results are shown in Table 3.CSA does not have the hepatic and renal function of mouse as shown in Table 3
There is obvious adverse effect, has the characteristics that hypotoxicity.
3 mouse hepatic and renal function testing result of table (numerical value indicated with mean value ± SED, n=9-10)
Embodiment 4
The present embodiment analyzes the pharmacokinetic properties of CSA.
It is clinically more to use Nintedanib: 1H- Indole-6-carboxylic acid, 2,3- dihydro -3- [[[4- [methyl [(4- methyl -
1- piperazinyl) acetyl group] amino] phenyl] amino] phenylmethylene] -2- oxygen -, methyl esters, (3Z)-treats idiopathic lung fiber
Change, the more clinical line anti-fibrosis drug Nintedanib of the imidazopyrimidine analog derivative that the present invention synthesizes possesses more preferably medicine
The characteristics of for dynamics and hypotoxicity.
C57 mouse Compound Nintedanib and CSA are given with the dosage stomach-filling of 50mg/Kg/d, before administration and is given respectively
Different time points venous blood collection after medicine, separated plasma use ZORBAXSB-C18 chromatographic column for splitter, with acetonitrile -0.1% three
Fluoroacetic acid-water (volume ratio 35:20:45) be mobile phase, flow velocity 1.0mL/min, Detection wavelength 286nm, 35 DEG C of column temperature, in alkali
It is detected after ethyl acetate extracts under the conditions of property.Pharmacokinetic parameters are calculated with DAS3.0.
Reach within about 2-4 hours maximal plasma concentration, the Absolute oral of 100mg dosage after the administration of Nintedanib capsule oral
Availability is 4.69%, and Cpss is reached at least upon administration 1 week, and end-stage half-life period is 10 to 15 hours.And this
It can reach maximum plasma concentration in 0.5 hour after invention synthesis CSA administration, and the absolute bioavailability of 50mg dosage is
54.51%, when successive administration, reach steady state plasma concentration two days later, end-stage half-life period is 72 hours or more.And Nintedanib is normal
See gastrointestinal tract and liver and gallbladder adverse reaction, thereby increases and it is possible to influence fecundity, pregnant woman's disabling.And imidazopyrimidine synthesized by the present invention
Analog derivative has no obvious adverse reaction, and pregnant woman is available, has a clear superiority.
Claims (3)
1. a kind of imidazopyrimidine analog derivative for preventing and treating pulmonary fibrosis, which is characterized in that the structural formula of the derivative such as formula (I)
The shown or derivative is formula (I) compound represented pharmaceutically acceptable salt,
2. preventing and treating the imidazopyrimidine analog derivative of pulmonary fibrosis according to claim 1, which is characterized in that the formula (I)
Pharmaceutically acceptable salt is formula (I) compound represented and hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, lemon to compound represented
Acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or Ah
The addition salts that Wei's acid is formed.
3. application of the imidazopyrimidine analog derivative as claimed in claim 1 or 2 in the drug of preparation prevention and treatment pulmonary fibrosis.
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Cited By (4)
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| CN114588161A (en) * | 2020-12-07 | 2022-06-07 | 四川大学华西医院 | Hypoxanthine derivative with effect of preventing and treating pneumonia |
| CN114588160A (en) * | 2020-12-07 | 2022-06-07 | 四川大学华西医院 | Hypoxanthine derivative with anti-pulmonary fibrosis effect |
| WO2023168786A1 (en) * | 2022-03-11 | 2023-09-14 | 四川大学华西医院 | Use of 1,7-dihydro-6h-purin-6-one compounds in preparation of anti-pulmonary fibrosis drug |
| WO2023169557A1 (en) * | 2022-03-11 | 2023-09-14 | 四川易阿索医药科技有限公司 | Use of hypoxanthine compound in preparation of drug for treating pulmonary fibrosis |
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| CN114588161A (en) * | 2020-12-07 | 2022-06-07 | 四川大学华西医院 | Hypoxanthine derivative with effect of preventing and treating pneumonia |
| CN114588160A (en) * | 2020-12-07 | 2022-06-07 | 四川大学华西医院 | Hypoxanthine derivative with anti-pulmonary fibrosis effect |
| WO2023168786A1 (en) * | 2022-03-11 | 2023-09-14 | 四川大学华西医院 | Use of 1,7-dihydro-6h-purin-6-one compounds in preparation of anti-pulmonary fibrosis drug |
| WO2023169557A1 (en) * | 2022-03-11 | 2023-09-14 | 四川易阿索医药科技有限公司 | Use of hypoxanthine compound in preparation of drug for treating pulmonary fibrosis |
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