CN107573322A - Imatinib dinitrogen oxide, preparation method and use - Google Patents
Imatinib dinitrogen oxide, preparation method and use Download PDFInfo
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- CN107573322A CN107573322A CN201710794276.5A CN201710794276A CN107573322A CN 107573322 A CN107573322 A CN 107573322A CN 201710794276 A CN201710794276 A CN 201710794276A CN 107573322 A CN107573322 A CN 107573322A
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Abstract
Application the present invention relates to Imatinib nitrogen oxides and preparation method thereof and in medicine, in particular to the Imatinib dinitrogen oxide or its pharmaceutically acceptable salt shown in formula (I), its preparation method, pharmaceutical composition and the compounds of this invention comprising it are preparing the purposes in treating medicine for treating diabetic nephropathy.
Description
Technical field
The invention belongs to drug field, and in particular to Imatinib dinitrogen oxide, its preparation method and its as medicine
Especially as the purposes for preparing treatment and prevention medicine for treating diabetic nephropathy.
Background technology
Imatinib is researched and developed by Novartis Co., Ltd, is dyed in May, 2001 in granted list in the U.S. for treating late period Philadelphia
The positive chronic myelocytic leukemia (CML) of body or the chronic phase patient of alpha-interferon therapy failure.2 months 2002, FDA passed through
Accelerate approval approach approval treatment with imatinib late period or transfer Gastrointestinal Stromal cell tumour (GIST), the same period is also quickly by Europe
Alliance's patent medicine evaluates committee's approval.2008, FDA ratified it further through acceleration approval approach and is used to be possible to radical resection
But increased patient GIST of risk of relapse, obtain within 2011 USA and EU and ratify its treatment ALL paediatrics
Patient.Because it is to the revolutionary therapeutic effects of CML, 10 years survival rates of CML patient can be made to be greatly prolonged up to 85%~90%
The life cycle of patient, and its side effect is also greatly reduced relative to interferon therapy, therefore, Imatinib, which is quickly become, to be controlled
Treat the heavy bomb drugs of leukaemia.In China, Imatinib is in granted listing in 2002, trade name Gleevec, for treating
CML and gastrointestinal stromal tumor.
The chemical name of Imatinib is：4- [(4- methyl isophthalic acids-piperazinyl) methyl]-N- [4- methyl -3- [[4- (3- pyrroles
Piperidinyl) -2- pyrimidine radicals] amino] phenyl]-benzamide, there is structure shown in formula (II)：
Imatinib is easily oxidized under illumination condition, and the oxidation product now reported has pyridine 1- positions nitrogen oxides formula
(III) compound and piperazine 4- positions nitrogen oxides formula (IV) compound, its structure are as follows：
So far
Untill the present, have no that the separation about Imatinib pyridine 1- positions and pyrimidine 3- positions dinitrogen oxide, structural confirmation and application thereof are ground
The relevant report studied carefully.
The content of the invention
Present invention aims at a kind of Imatinib dinitrogen oxide or its pharmaceutically acceptable salt is provided, there is formula
(I) structure shown in：
The invention further relates to the method for formula (I) compound, this method comprises the following steps：
(1) chlorobenzoyl chloride 1a obtains compound 1b with thionyl chloride heating reflux reaction under catalyst action；
(2) compound 1c and 1b acylation reaction occur in the presence of acid binding agent obtain compound 1d；
(3) compound 1d is dissolved in dichloromethane, -20 DEG C of addition metachloroperbenzoic acids of temperature control, is warmed to room temperature generation nitrogen
Oxidation reaction, column chromatography afford compound 1e；
(4) compound 1e is heated to reflux generation hydrolysis and obtains compound 1f in the presence of 4mol/L hydrochloric acid；
(5) compound 1g obtains compound 1h with thionyl chloride heating reflux reaction under catalyst action；
(6) compound 1f and compound 1h generations acylation reaction obtains formula (I) compound.
Preferred scheme of the present invention, the catalyst described in step (1) and (5) are DMF, catalyst and two
The volume ratio of chlorine sulfoxide is 1:100.
Preferred scheme of the present invention, the acid binding agent described in step (2) are selected from pyridine, triethylamine, sodium carbonate, sodium acid carbonate, carbon
Sour potassium, sodium hydroxide or potassium hydroxide, preferably acid binding agent are triethylamine.
In step (3), make oxidant using metachloroperbenzoic acid, first engage in reaction for pyridine 1- positions nitrogen oxidation it is anti-
Should, secondly react for pyrimidine 3- positions nitrogen oxidation, reacted again for pyrimidine 1- positions nitrogen oxidation.
The mol ratio of preferred scheme of the present invention, step (3) compound 1d and metachloroperbenzoic acid is 1：2~3, further
The mol ratio of preferred compound 1d and metachloroperbenzoic acid is 1：2.4.
Preferred scheme of the present invention, the solvent of described column chromatography elution is that volume ratio is 1:20 methanol and dichloromethane
Mixed solvent.
The invention further relates to Imatinib dinitrogen oxide or its pharmaceutically acceptable salt to be used as standard items or reference substance
Application.
The present invention relates to a kind of pharmaceutical composition, described composition includes Imatinib dinitrogen oxide formula (I) chemical combination
Thing or its pharmaceutically acceptable salt, and one or more kinds of pharmaceutically acceptable carriers and/or excipient.
The present invention relates to formula (I) compound or its pharmaceutically acceptable salt to prepare prevention or treatment diabetic nephropathy medicine
Purposes in thing.
The invention further relates to compound pharmaceutically acceptable salt, described salt shown in formula (I) to include, but are not limited to hydrochloric acid
Salt, phosphate, acetate, trifluoroacetate, fumarate, maleate, malate, citrate, succinate, first sulphur
Hydrochlorate, benzene sulfonate or tosilate；It is preferred that mesylate.
Brief description of the drawings
Fig. 1 is the H of formula (I) compound1- NMR spectra.
Fig. 2 is the MS collection of illustrative plates of formula (I) compound.
Fig. 3 is influence datagram of the effect experiment each group to Diabetic Nephropathy rat body weight.
Embodiment
Below by embodiment, the invention will be further described.It should be understood that the embodiment of the present invention is only to use
In the explanation present invention, rather than limitation of the present invention or changes simple replacement under the concept thereof of the present invention to the present invention
Enter to belong to the scope of protection of present invention.
The structure of compound by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) determines.NMR displacements (δ) are with 10-6
(ppm) unit provides.NMR measure is to use (Bruker-500MHz NMR) nuclear magnetic resonance spectrometer, and measure solvent is that deuterated dimethyl is sub-
Sulfone (DMSO-d6), inside it is designated as tetramethylsilane (TMS)；MS measure is with Agilent6120B (ESI).
Embodiment 1
The synthesis of chlorobenzoyl chloride (1b)
Benzoic acid 1a is added into 100mL there-necked flasks (on 5g, 0.041mol, Sigma-Aldrich Sigma-Aldrich
Extra large trade Co., Ltd), thionyl chloride (30mL) and catalyst n, dinethylformamide (0.3mL), heating reflux reaction 3 it is small
When, room temperature is down to, removes thionyl chloride under reduced pressure, obtains chlorobenzoyl chloride (1b) 5.75g of weak yellow liquid shape.
Embodiment 2
The synthesis of N- [4- methyl -3- [[4- (3- pyridine radicals) -2- pyrimidine radicals] amino] phenyl] benzamide (1d)
1c (7.5g, 0.027mol, Suzhou Xin Kai biological medicine technologies Co., Ltd) is put into 250mL there-necked flasks, added
Interior 0~3 DEG C of temperature is down in tetrahydrofuran (135mL) and triethylamine (7.53mL), stirring, is added dropwise the four of 1b (5.75g, 0.041mol)
Hydrogen furans (57mL) solution, interior temperature control system is below 5 DEG C, and drop finishes, and is warming up to 20~25 DEG C, insulation reaction 3 hours, stirring
Lower addition purified water (415mL), is down to room temperature, filters, purifying water washing (30mL × 2), and 75~80 DEG C are dried in vacuo 2 hours,
Obtain N- [4- methyl -3- [[4- (3- pyridine radicals) -2- pyrimidine radicals] amino] phenyl] benzamide (1d) of yellow solid
10g, yield 97%.
Embodiment 3
N- [4- methyl -3- [[4- (1- oxygen -3- pyridine radicals) -3- oxygen -2- pyrimidine radicals] amino] phenyl] benzamide (1e)
Synthesis
1d (10g, 0.027mol) is put into 500mL there-necked flasks, dichloromethane (350mL) is added, is added under the conditions of -20 DEG C
Metachloroperbenzoic acid (11.2g, 0.065mol, Sigma-Aldrich Sigma-Aldrich Shanghai trade Co., Ltd), rise
To room temperature, react 72 hours, filtering, filtrate decompression is concentrated to dryness, purified with silica gel column chromatography, and eluant, eluent is methanol：Dichloro
Methane=1:20 (volume ratio, v/v), obtain yellow solid N- [4- methyl -3- [[4- (1- oxygen -3- pyridine radicals) -3- oxygen -
2- pyrimidine radicals] amino] phenyl] benzamide (1e) 5.47g, yield 49%.
Embodiment 4
The synthesis of 4- methyl -3- [[4- (1- oxygen -3- pyridine radicals) -3- oxygen -2- pyrimidine radicals] amino] aniline (1f)
1e (5.47g, 0.013mol) is put into 500ml there-necked flasks, adds n-butanol (115mL) and 4mol/L hydrochloric acid
(115mL), heating reflux reaction 48 hours, is down to room temperature, and pressurization is concentrated to dryness, and obtains brown oil, grease is dissolved in pure
Change water (130mL), filtering, pH is adjusted to 8~9 with 4mol/L sodium hydroxide solution, filtering, purifies water washing (30mL by filtrate
× 2), 75~80 DEG C are dried in vacuo 2 hours, are purified with silica gel column chromatography, eluant, eluent is methanol：Dichloromethane=1:20 (bodies
Product ratio, v/v), obtain 4- methyl -3- [[4- (1- oxygen -3- pyridine radicals) -3- oxygen -2- pyrimidine radicals] amino] benzene of yellow solid
Amine (1f) 1.83g, yield 46%.
Embodiment 5
The synthesis of 4- [(4- methyl isophthalic acids-piperazinyl) methyl] chlorobenzoyl chloride dihydrochloride (1h)
Imma acid 1g (5g, 0.021mol, pacifying resistance to Jilin Chemical) is put into 100mL there-necked flasks, adds thionyl chloride (35mL)
And catalyst n, dinethylformamide (0.3mL), heating reflux reaction 22 hours, room temperature is down to, filtered, n-hexane washing
(10mL × 2), 45~50 DEG C are dried in vacuo 2 hours, obtain 4- [(4- methyl isophthalic acids-piperazinyl) methyl] benzoyl of white solid
Chlorine dihydrochloride (1h) 5.1g, yield 95%.
Embodiment 6
4- [(4- methyl isophthalic acids-piperazinyl) methyl]-N- [4- methyl -3- [[4- (1- oxygen -3- pyridine radicals) -3- oxygen -2- pyrimidines
Base] amino] phenyl] and benzamide formula (I) synthesis
1f (1.83g, 0.006mol) is put into 100mL there-necked flasks, adds purified water (31mL), interior temperature 0~3 is down in stirring
DEG C, 1h (3.9g, 0.015mol) is added portionwise, is stirred at room temperature 2 hours, filters, filtrate adds acetone (16mL), it is heated to 45~
50 DEG C, ammoniacal liquor is added dropwise, until cloud point occurs, is cooled to room temperature, stirring and crystallizing 2 hours, filters, with purifying water washing (10mL ×
2), 75~80 DEG C be dried in vacuo 2 hours, obtain yellow solid 4- [(4- methyl isophthalic acids-piperazinyl) methyl]-N- [4- methyl-
3- [[4- (1- oxygen -3- pyridine radicals) -3- oxygen -2- pyrimidine radicals] amino] phenyl] benzamide formula (I) 2.29g, yield 73%,
HPLC：99.2%.
1H NMR(DMSO-d6, 500MHz)：δ 2.17 (s, 3H), δ 2.30 (s, 3H), δ 2.35 (m, 8H), δ 3.55 (s,
2H), δ 7.31 (d, 1H), δ 7.50 (m, 4H), δ 7.66 (d, 1H), δ 8.00 (d, 2H), δ 8.18 (d, 1H), δ 8.28 (d, 1H), δ
8.63 (s, 1H), δ 8.75 (d, 1H), δ 8.89 (s, 1H), δ 9.75 (s, 1H), δ 10.26 (s, 1H).
MS m/z(ESI)：526.2[M+H].
The test of pesticide effectiveness of embodiment 7
(a) experimental animal and model
Diabetic nephropathy rats animal model is caused using unilateral nephrectomy plus intraperitoneal injection Streptozotocin.It is male to choose adult
Property SD rats 50, body weight about 260g, be purchased from Beijing experimental animal company of dimension tonneau China, be randomly divided into normal group, model group and
Administration group, every group 10.
Using single intraperitoneal injection Streptozotocin 8 weeks, diabetic nephropathy rats are established, sugar was formed at first 4 weeks
Urine is sick (blood sugar concentration is not less than 16.7mmol/L, is finally reached 25mmol/L), forms diabetic nephropathy model within latter 4 weeks.
(b) experimental program
Next day after diabetes model replicates successfully, Formulas I, Formula II and formula made of administration group rat oral gavage ultra-pure water solution
Each 200mg/kg of III, model group and normal group give isometric ultra-pure water.After observing 8 weeks, rat body weight change is investigated, is received
Collect sample, experiment terminates the previous day and twenty-four-hour urine liquid is accurately collected with metabolic cage, carries out twenty-four-hour urine Protein Detection；Rat limosis
After 8 hours, pluck eyeball and take blood 2mL, leave and take serum after centrifugation, make biochemical kidney function test, the results are shown in Table 1.
(c) experimental result
The influence of the formula of table 1 (I), formula (II) and formula (III) compound to Diabetic Nephropathy Renal Function in Rats
| Group | Blood glucose (mmol/L) | Blood urea nitrogen (mmol/L) | Serum creatinine (μm ol/L) | Albuminuria (g/L) |
| Normal group | 5.14±0.42 | 5.32±0.73 | 22.33±1.52 | 10.92±0.91 |
| Model group | 40.78±4.77 | 19.24±2.81 | 50.79±6.11 | 118.63±10.24 |
| Formula (I) administration group | 5.97±2.13 | 6.03±0.57 | 24.61±1.92 | 17.18±2.69 |
| Formula (II) administration group | 36.42±1.58 | 15.36±1.03 | 42.57±2.41 | 89.34±1.16 |
| Formula (III) administration group | 33.16±2.94 | 12.85±0.94 | 36.15±1.68 | 57.29±4.21 |
As it can be seen from table 1 after testing 8 weeks, model group is equal compared with normal group blood glucose, blood urea nitrogen, serum creatinine and albuminuria
It is significantly raised, illustrate the formation of rat diabetes renal dysfunction；Formula (I) administration group can significantly reduce blood compared with model group
Sugar, blood urea nitrogen, serum creatinine and Urine proteins, and effect is better than formula (II) administration group and formula (III) administration group；The above results show
Formula (I) compound can effectively improve the renal function of diabetic nephropathy rats.
From figure 3, it can be seen that after testing 8 weeks, model group rat body weight compared with normal group is decreased obviously；Formula (I) is administered
Group body weight compared with model group substantially increases, and is given higher than formula (II) administration group and formula (III) administration group, normal group with formula (I)
There is no significant difference between medicine group；The above results show that formula (I) compound can effectively weaken the body weight of diabetic nephropathy rats
Decline.
Claims (10)
1. a kind of Imatinib dinitrogen oxide or its pharmaceutically acceptable salt, there is structure shown in formula (I)：
2. a kind of method of formula (I) compound prepared described in claim 1, this method comprise the following steps：
(1) chlorobenzoyl chloride 1a obtains compound 1b with thionyl chloride heating reflux reaction under catalyst action；
(2) compound 1c and 1b acylation reaction occur in the presence of acid binding agent obtain compound 1d；
(3) compound 1d is dissolved in dichloromethane, -20 DEG C of addition metachloroperbenzoic acids of temperature control, is warmed to room temperature generation nitrogen oxidation
Reaction, column chromatography afford compound 1e；
(4) compound 1e is heated to reflux generation hydrolysis and obtains compound 1f in the presence of 4mol/L hydrochloric acid；
(5) compound 1g obtains compound 1h with thionyl chloride heating reflux reaction under catalyst action；
(6) compound 1f and compound 1h generations acylation reaction obtains formula (I) compound.
3. according to the method for claim 2, it is characterised in that the catalyst described in step (1) and (5) is N, N- dimethyl
The volume ratio of formamide, catalyst and thionyl chloride is 1:100.
4. according to the method for claim 2, it is characterised in that acid binding agent described in step (2) be selected from pyridine, triethylamine,
Sodium carbonate, sodium acid carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
5. according to the method for claim 4, it is characterised in that the acid binding agent described in step (2) is triethylamine.
6. according to the method for claim 2, it is characterised in that step (3) compound 1d and metachloroperbenzoic acid rub
You are than being 1：2~3, the solvent of described column chromatography elution is that volume ratio is 1:The mixing of 20 methanol and dichloromethane is molten
Agent.
7. according to the method for claim 6, it is characterised in that step (3) compound 1d and metachloroperbenzoic acid rub
You are than being 1：2.4.
8. the Imatinib dinitrogen oxide or its pharmaceutically acceptable salt described in claim 1 are used as standard items or reference substance
Application.
9. a kind of pharmaceutical composition, in described composition comprising the Imatinib dinitrogen oxide described in claim 1 or its
Pharmaceutically acceptable salt, and one or more kinds of pharmaceutically acceptable carriers and/or excipient.
10. formula (I) compound or its pharmaceutically acceptable salt described in claim 1 are preparing prevention or treatment diabetogenous nephrosis
Purposes in medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109956898A (en) * | 2017-12-22 | 2019-07-02 | 上海海雁医药科技有限公司 | Immunomodulator and its preparation method and purposes pharmaceutically |
| CN111039810A (en) * | 2019-12-13 | 2020-04-21 | 厦门蔚嘉制药有限公司 | Preparation process of praziquantel intermediate |
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| WO2001064200A2 (en) * | 2000-03-03 | 2001-09-07 | Novartis Ag | Use of pdgf receptor tyrosine kinase inhibitors for the treatment of diabetic nephropathy |
| CN1646519A (en) * | 2002-01-23 | 2005-07-27 | 诺瓦提斯公司 | N-oxyde of N-phenyl-2-pyrimidine-amine derivatives |
| US20140121215A1 (en) * | 2012-10-25 | 2014-05-01 | Cadila Healthcare Limited | Process for the preparation of amorphous imatinib mesylate |
-
2017
- 2017-09-06 CN CN201710794276.5A patent/CN107573322A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001064200A2 (en) * | 2000-03-03 | 2001-09-07 | Novartis Ag | Use of pdgf receptor tyrosine kinase inhibitors for the treatment of diabetic nephropathy |
| CN1646519A (en) * | 2002-01-23 | 2005-07-27 | 诺瓦提斯公司 | N-oxyde of N-phenyl-2-pyrimidine-amine derivatives |
| US20140121215A1 (en) * | 2012-10-25 | 2014-05-01 | Cadila Healthcare Limited | Process for the preparation of amorphous imatinib mesylate |
Non-Patent Citations (3)
| Title |
|---|
| BERTRAND ROCHAT等: ""In vitro Biotransformation of Imatinib by the Tumor Expressed CYP1A1 and CYP1B1"", 《BIOPHARMACEUTICS & DRUG DISPOSITION》 * |
| W.J. SZCZEPEK等: ""Identification of imatinib mesylate degradation products obtained under stress conditions"", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
| 孙世澜等主编: "《肾衰竭诊断治疗学》", 30 April 2012 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109956898A (en) * | 2017-12-22 | 2019-07-02 | 上海海雁医药科技有限公司 | Immunomodulator and its preparation method and purposes pharmaceutically |
| CN111039810A (en) * | 2019-12-13 | 2020-04-21 | 厦门蔚嘉制药有限公司 | Preparation process of praziquantel intermediate |
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