CN109806397A - SGLT2 inhibitor combines the purposes in the drug of the diseases such as preparation treatment hypertension with ARB - Google Patents
SGLT2 inhibitor combines the purposes in the drug of the diseases such as preparation treatment hypertension with ARB Download PDFInfo
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- CN109806397A CN109806397A CN201811373251.9A CN201811373251A CN109806397A CN 109806397 A CN109806397 A CN 109806397A CN 201811373251 A CN201811373251 A CN 201811373251A CN 109806397 A CN109806397 A CN 109806397A
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- compound
- angiotensin
- receptor antagonist
- irbesartan
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Abstract
The present invention relates to SGLT2 inhibitors to combine the purposes in the drug of the diseases such as preparation treatment hypertension with ARB.Specifically, SGLT2 inhibitor of the invention is selected from compound (1) or its compound or its officinal salt or its stereoisomer, and angiotensin II receptor antagonist (ARB) is selected from Losartan, Valsartan, Irbesartan, Candesartan, Tasosartan, Azilsartan, Eprosartan, Olmesartan or Telmisartan.
Description
Technical field
The present invention relates to SGLT2 inhibitors to combine in preparation prevention with angiotensin II receptor antagonist or treat high blood
Purposes in the drugs of diseases such as pressure.
Background technique
Hypertension is a kind of common disease.Estimate according to WTO, there are about 20% adults to suffer from hypertension, and in making a definite diagnosis patient, has
75% fails to be effectively treated.Because the disease incidence 50% that hypertension died accounts for about cardiovascular disease rises year by year, disability rate
Also in rising trend, the death rate is high.According to domestic clinical statistics, blood pressure declines 1.20/0.67Kpa, can about prevent every year
450000 people die of stroke.There is studies have shown that blood pressure to reduce 0.67Kpa, cardiovascular danger decline 30%.With the raising of blood pressure,
Stroke, the risk of coronary artery events increase with it, hypertension be coronary heart disease, cranial vascular disease, renal vascular diseases it is main
Pathogenic factor and adult mortality, it is invalid the main reason for.Currently, clinically used depressor has diuretics, calcium ion antagonism
Agent (CCB), angiotensin converting enzyme inhibitor (ACEI), Angiotensin Ⅱ receptor antagonist (ARB), beta-blocker,
α receptor blocker etc..
Diabetes are a kind of progressive diseases with a variety of potential pathophysiological defects, and diabetic nephropathy (DKD) is 2
One of most common complication of patients with type Ⅰ DM.Diabetic nephropathy will lead to injury of kidney, and glomerular filtration rate reduces and lasting egg
Albiduria.The cause of disease of diabetic nephropathy includes environmental pollution, genetic predisposition, main metabolic and hemodynamic factors etc..Therefore
The main purpose for treating treatment diabetic nephropathy is control metabolism and hemodynamic abnormalities.Currently, clinically used treatment sugar
Urinating sick nephrosis drug has antihyperglycemic agents (AHAs), angiotensin converting enzyme inhibitor (ACEI), angiotensin-ii-receptor
Antagonist (ARB) etc..
Sodium glucose co-transporter 2 white 2 (SGLT2) inhibitor is a kind of blood sugar tube with obvious single therapy advantage
Drug is managed, the inhibitor of SGLT-2 can block proximal convoluted tubule to the reabsorption of glucose and extra grape is discharged by urine
Sugar, to achieve the purpose that reduce blood glucose.The inhibitor of SGLT-2 can also be combined with other drugs (such as ARB class drug) and treat
Diabetic nephropathy, and reduce cardiovascular risk.Honghong Zou etc. (Cardiovasc Diabetol (2017) 16:65)
It discloses the SGLT-2 such as Dapagliflozin, canagliflozin inhibitor and ARB is combined, for treating type-2 diabetes mellitus hypertension and glycosuria
Sick nephrosis.
Combine the present invention provides a kind of new SGLT2 inhibitor with angiotensin II receptor antagonist and prevents in preparation
Or the purposes in the drug of diseases such as treatment hypertension, wherein SGLT2 inhibitor is selected from compound (1) or its compound or it can
Pharmaceutical salts or its stereoisomer, preparation method and the purposes for diabetic nephropathy disclose in CN102482290A.
Summary of the invention
The present invention provides SGLT2 inhibitors to combine with angiotensin II receptor antagonist in preparation prevention or treatment height
Purposes in the drug of blood pressure or diabetic nephropathy, wherein the SGLT2 inhibitor be selected from compound (1) or its compound or
Its officinal salt or its stereoisomer,
In some embodiments, the angiotensin II receptor antagonist can be Losartan (losartan),
Valsartan (valsartan), Irbesartan (irbesartan), Candesartan (candesartan), Tasosartan
(tasosartan), Azilsartan (Azilsartan), Eprosartan (eprosartan), Olmesartan (Olmesartan)
Or Telmisartan (telmisartan) etc., preferred Irbesartan.
The angiotensin II receptor antagonist drug can be free state or pharmaceutically acceptable salt, compound
Object, precursor forms.
In the preferred embodiment of the present invention, compound (1) is combined with angiotensin II receptor antagonist for treating
In hypertension or diabetic nephropathy therapeutic process, (including but not limited to En Gelie is net, card lattice with other similar SGLT2 inhibitors
Column are net, glug column are net etc.) it is compared with ARB (including but not limited to Losartan, Valsartan, Irbesartan, Azilsartan etc.), have
Preferably decompression and diabetic nephropathy therapeutic effect.
The hypertension can be essential hypertension or secondary hypertension.
In the preferred embodiment of the present invention, the compound (1) or its compound or its officinal salt or its solid are different
Structure body and the weight ratio of angiotensin II receptor antagonist are selected from 0.01:1-10:1, preferably 1:1,9:10,4:5,3:4,7:
10、2:3、3:5、8:15、1:2、9:20、2:5、3:8、7:20、1:3、3:10、4:15、1:4、7:30、9:40、1:5、7:40、1:
6,3:20,2:15,1:8,1:10,3:40,1:15,1:20,1:30,1:40, more preferable 2:5,3:5,1:5,1:2,9:20,1:3,
3:10、3:20、4:15、1:4、1:10、1:20、10:1。
In currently preferred another embodiment, the compound (1) or its compound or its officinal salt or its
The dosage range of stereoisomer is selected from 1-150mg, preferably is selected from 1-50mg；The dosage of the angiotensin II receptor antagonist
Range is selected from 1-500mg, preferably is selected from 50-300mg.
In above-mentioned preferred embodiment scheme, the compound (1) or its compound or its officinal salt or it is three-dimensional
The dosage of isomers be selected from 1.25mg, 2.5mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 50mg,
60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, preferably 1mg, 2mg, 2.5mg, 5mg, 7.5mg, 10mg,
15mg,20mg,25mg,30mg,35mg,40mg,50mg；The dosage of the angiotensin II receptor antagonist be selected from 10mg,
20mg、25mg、30mg、40mg、50mg、60mg、70mg、75mg、80mg、90mg、100mg、110mg、120mg、125mg、
130mg、140mg、150mg、160mg、170mg、175mg、180mg、190mg、200mg、225mg、250mg、260mg、
270mg、275mg、280mg、290mg、300mg、310mg、320mg、325mg、330mg、340mg、350mg、375mg、
400mg, 425mg, 450mg, 475mg, 500mg, preferably 25mg, 30mg, 40mg, 50mg, 60mg, 70mg, 75mg, 80mg,
90mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、175mg、180mg、190mg、
200mg、225mg、250mg、260mg、270mg、275mg、280mg、290mg、300mg、310mg、320mg、325mg、
330mg、340mg、350mg。
The compound of the compound (1) can be the compound of compound (1) and proline, more preferable compound (1)
With the compound of L-PROLINE.
The officinal salt of the drug can be hydrochloride, phosphate, hydrophosphate, sulfate, disulfate, sulfurous acid
Salt, acetate, oxalates, malonate, valerate, glutamate, oleate, palmitate, stearate, laruate,
Borate, tosilate, mesylate, malate, tartrate, benzoate, embonate, salicylate,
Vanillate, mandelate, succinate, gluconate, Lactobionate or lauryl sulfonate.
United administration route of the present invention is selected from oral administration, parenteral, percutaneous dosing, described parenterally to give
Medicine includes but is not limited to be injected intravenously, be subcutaneously injected, intramuscular injection.
The invention further relates to compound (1) or its compound or its officinal salt or its stereoisomer and blood vessel are tight
Purposes of the element II receptor antagonist combination in the drug of preparation prevention or treatment hypertension or diabetic nephropathy is opened, wherein chemical combination
The dosage rate of object (1) or its compound or its officinal salt or its stereoisomer can be once a day, two times a day, one
Day three times, weekly, two weeks once, once in three weeks or once a month, the dosage rate of angiotensin II receptor antagonist
Can be once a day, two times a day, three times per day, weekly, two weeks once, once in three weeks or once a month.
In some embodiments, the administration of compound (1) or its compound or its officinal salt or its stereoisomer
The frequency can be once a day, and the dosage rate of angiotensin II receptor antagonist can be once a day.
Term " joint " is a kind of administration mode, refers to the SGLT2 suppression that at least one dosage is given in the certain time time limit
The angiotensin II receptor antagonist of preparation and at least one dosage, wherein two kinds of drugs all show that pharmacotoxicological effect produces
Raw pharmacological action.This time time limit can be a dosage period, such as 24 hours.Two kinds of drugs can simultaneously or sequentially be given
Medicine.
In scheme of the present invention, the described joint it is optional also include other components, the other components include but
It is not limited to other antihypertensive medicine, antidiabetic drugs etc..
The present invention also provides SGLT2 inhibitors to combine with angiotensin II receptor antagonist in preparation prevention or treatment
Purposes in the drug of hypertension or diabetic nephropathy, wherein the SGLT2 inhibitor is selected from compound (1) or its compound
Or its officinal salt or its stereoisomer, the angiotensin II receptor antagonist are Irbesartan.
The present invention also provides a kind of methods for treating hypertension or diabetic nephropathy, including apply institute of the present invention to patient
The SGLT2 inhibitor and Angiotensin Ⅱ receptor antagonist stated, wherein SGLT2 inhibitor is selected from compound (1) or its is compound
Object or its officinal salt or its stereoisomer.
The invention further relates to one kind to include compound (1) or its compound or its officinal salt or its stereoisomer, blood
The pharmaceutical composition of angiotensin II receptor antagonist and one or more pharmaceutical carriers, excipient, diluent.The drug
Pharmaceutically acceptable any dosage form can be made in composition.For example, can be formulated as tablet, capsule, pill, granule,
Solution, suspension, syrup, injection (including injection, injection sterile powder and concentrated solution for injection), suppository, suction
Enter agent or spray.
It is of the present invention to contain compound (1) or its compound or its officinal salt or its stereoisomer, vasotonia
The pharmaceutical composition of plain II receptor antagonist, can be administered alone, or use with one or more therapeutic agents.
The present invention also provides a kind of medicine package boxes, wherein being packaged with SGLT2 inhibitor of the present invention and blood vessel
The pharmaceutical composition of Angiotensin Ⅱ receptor antagonist, wherein SGLT2 inhibitor is selected from compound (1) or its compound or it can medicine
With salt or its stereoisomer.
The present invention is medication combined by compound (1) or its compound or its officinal salt or its stereoisomer and ARB class
Administration, to enhance antihypertensive effect, and improves the therapeutic effect of diabetic nephropathy.
Specific embodiment
Embodiment 1: compound (1) and Irbesartan are administered in combination and lure with respective be administered alone streptozotocin (STZ)
The drug action of spontaneous hypertensive rat (SHR) diabetic nephropathy and blood pressure lowering led is studied.
1. test medicine
Medicine name: the compound of compound (1) and L-PROLINE, the preparation of the method according to disclosed in WO2016050134；
Irbesartan is provided by Hengrui Medicine Co., Ltd., Jiangsu Prov..
Preparation method: the compound of compound (1) and L-PROLINE is with 0.5%CMC-Na/1%Tween's 80 (w/v)
Deionized water is prepared；Irbesartan is prepared with the deionized water of 0.5%CMC-Na/1%Tween 80 (w/v).
2. experimental animal
Wistar Kyoto rat: male, buying the age is 8~9 week old, and buying weight is 175-205g；
SHR: male, buying the age is 8~9 week old, and buying weight is 175-205g.
It is purchased from Beijing Vital River Experimental Animals Technology Co., Ltd., production licence number (WKY): SCXK (capital)
2016-0006, production licence number (SHR): SCXK (capital) 2016-0011；Quality certification number, WKY:11400700243678；
SHR:11400700243675,11400700245036.
Feeding environment: temperature: 20~26 DEG C of temperature of control；Relative humidity: control relative humidity 40%~70%；Illumination:
Automatic illumination, every 12h light and shade alternating, 8:00a.m. turn on light, and 8:00p.m. turns off the light.
3. experimental procedure
After a week, (Wistar Kyoto rat is not after SHR fasting 16h for SHR and Wistar Kyoto rat adaptive feeding
Processing), 60mg/kg STZ is injected intraperitoneally according to weight and carries out modeling.
After STZ modeling 3-5 days, the successful SHR rat of diabetes model (random blood sugar is higher than 16.6) is chosen, is rejected excessively high
Animal not up to standard is grouped at random by blood glucose value.It is divided into Normal group, model control group, compound (1) proline salt list
Medicine group (dosage 10mg/kg), Irbesartan list medicine group (dosage 30mg/kg, 20mg/kg), compound (1) proline
Salt+Irbesartan joint group (dosage 10mg/kg+30mg/kg, 10mg/kg+20mg/kg), every group 10.Every group of administration
Volume is 10ml/kg, and wherein combination group compound (1) and Irbesartan administered volume are 5ml/kg.Daily gastric infusion 1
Secondary, totally 12 weeks, wherein Normal group, model control group are oral gave 0.5%CMC-Na/1%Tween 80.
4. Testing index:
It is as follows to be grouped animal Testing index:
Weight: measuring once a week, i.e., before administration, administration the 1st, 2,3,4,5,6,7,8,9,10,11,12 week；It ingests
Amount, amount of drinking water, random blood sugar, albuminuria (total protein and albumin): measuring once every two weeks, i.e., before administration, administration the 2nd,
4,6,8,10,12 weeks；Fasting blood-glucose, blood pressure, serum creatinine, urine creatinine, urea nitrogen: monthly measuring, i.e., before administration, gives
Medicine the 4th, 8,12 week；Food ration and amount of drinking water are the food ration and amount of drinking water of the primary r for 24 hours of measurement in two weeks；Measure serum creatinine, urine
When creatinine, urea nitrogen, rat needs fasting 8-10hr；2-4hr is measured blood pressure after administration.
5. pathologic finding index:
After administration in 12 weeks, all animals are put to death, kidney is taken to weigh, and carry out pathological score (between glomerulus, renal tubule, kidney
Matter etc.).
6. experimental result:
6.1. compound (1) and Irbesartan are combined the influence to rat fasting blood-glucose
At the end of administration, compound (1)+Irbesartan combination group fasting blood-glucose is 8.8 ± 0.64mmol/L, with compound
(1) group (13.4 ± 1.35mmol/L) is compared significant decrease (P < 0.05) with Irbesartan group (11.0 ± 0.59mmol/L), and two
Medicine combination group shows significantly to cooperate with the effect for reducing fasting blood-glucose.
1 rat fasting blood-glucose of table (mmol/L) (mean value ± SE)
Note: n=8~10, One-way ANOVA, compared with model control group, *: P < 0.05；*: P < 0.01；* *: P <
0.001.Compared with compound (1) group, #:P < 0.05；##:P < 0.01；###:P < 0.001.Compared with Irbesartan group, △: P <
0.05；△ △: P < 0.01；△ △ △: P < 0.001.
6.2 compounds (1) and Irbesartan are combined the influence to rat blood pressure
When being administered the 84th day, for compound (1)+Irbesartan combination group compared with Irbesartan list medicine group group, systolic pressure is aobvious
Writing reduces (P < 0.05).
2 rat blood pressure of table (mmHg) (mean value ± SE)
Note: n=8~10, One-way ANOVA, compared with model control group, *: P < 0.05；*: P < 0.01；* *: P <
0.001.Compared with compound (1) group, #:P < 0.05；##:P < 0.01；###:P < 0.001.Compared with Irbesartan group, △: P <
0.05；△ △: P < 0.01；△ △ △: P < 0.001.
6.3 compounds (1) and Irbesartan are combined on the pathological influence of rat kidney
Histotomy is subjected to PAS dyeing, carries out the marking of whole group Progression of Glomerulosclerosis, the results show that compound (1)+
Irbesartan group can significantly alleviate the sclerotic conditions of rat, and scoring situation can be dropped to by 3.0 ± 1.2 points of model control group
1.8 ± 0.7 points (P < 0.05).
Equally, it is dyed using PAS, analyzes the detailed sclerotic conditions of glomerulus of each animal.As the result is shown: compound
(1)+Irbesartan group can be relieved the sclerotic conditions of rat, and compound (1)+1 grade of Irbesartan group hardening ratio can
It is improved by the 38.2 ± 3.4% of model group to 42.8 ± 1.7%, and had compared with group is applied alone in compound (1) group, Irbesartan
Apparent statistical significance (P < 0.05).Greater than 2 grades hardening can drop to 4.8 ± 1.3% by the 10.5 ± 3.3% of model group,
Downward trend is obvious.
3. compound of table (1) and Irbesartan are combined influence (whole pathological score) pathological on rat kidney
Note: One-way ANOVA, n=8, *: P < 0.05vs model comparison.
4. compound of table (1) and Irbesartan combination influence pathological on rat kidney (individual hardening marking result)
(percentage,)
Note: One-way ANOVA, compared with model control group, n=8, * *: P < 0.01；* *: P < 0.001.With SGLT2
Group compares, ##:P < 0.01.Compared with Irbesartan group, △ △: P < 0.01.
7. experiment conclusion:
In SHR Hypertension Rats/diabetes model of STZ induction, compound (1) can cooperate with drop with Irbesartan combination
The blood pressure and fasting blood-glucose of low rat model, while the combination of two medicines also has synergistic effect to the improvement of glomerulosclerosis.
Claims (8)
1.SGLT2 inhibitor is combined with angiotensin II receptor antagonist in preparation prevention or treatment hypertension or diabetogenous nephrosis
Purposes in the drug of disease, wherein the SGLT2 inhibitor is selected from compound (1) or its compound or its officinal salt or it is vertical
Body isomers,
2. purposes according to claim 1, which is characterized in that it is husky that the angiotensin II receptor antagonist is selected from chlorine
Smooth, Valsartan, Irbesartan, Candesartan, Tasosartan, Azilsartan, Eprosartan, Olmesartan or Telmisartan,
It is preferred that Irbesartan.
3. purposes according to claim 1 or 2, which is characterized in that the compound (1) or its compound or its is pharmaceutically acceptable
Salt or its stereoisomer and angiotensin II receptor antagonist weight ratio are 0.01:1-10:1, preferably 1:1,9:10,4:5,
3:4、7:10、2:3、3:5、8:15、1:2、9:20、2:5、3:8、7:20、1:3、3:10、4:15、1:4、7:30、9:40、1:5、
7:40、1:6、3:20、2:15、1:8、1:10、3:40、1:15、1:20、1:30、1:40。
4. purposes according to claim 1 or 2, which is characterized in that the compound (1) or its compound or its is pharmaceutically acceptable
The dosage range of salt or its stereoisomer is selected from 1-150mg, preferably 1-50mg.
5. purposes according to claim 1 or 2, which is characterized in that the dosage of the angiotensin II receptor antagonist
Range is selected from 1-500mg, preferably 50-300mg.
6. purposes described in -5 any one according to claim 1, which is characterized in that the compound of the compound (1) is selected from
The compound of compound (1) and proline, the compound of more preferable compound (1) and L-PROLINE.
7. pharmaceutical composition includes compound (1) or its compound or its officinal salt or its alloisomerism described in claim 1
Body and angiotensin II receptor antagonist and one or more pharmaceutical excipient, diluent or carrier.
8. medicine package box, wherein being packaged with SGLT2 inhibitor of the present invention and Angiotensin Ⅱ receptor antagonist
Pharmaceutical composition, wherein SGLT2 inhibitor is selected from compound (1) or its compound or its officinal salt or its stereoisomer.
Applications Claiming Priority (4)
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| CN201711160583 | 2017-11-20 | ||
| CN2017111605834 | 2017-11-20 | ||
| CN201811047935X | 2018-09-07 | ||
| CN201811047935 | 2018-09-07 |
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| CN109806397A true CN109806397A (en) | 2019-05-28 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115894454A (en) * | 2021-09-06 | 2023-04-04 | 天地恒一制药股份有限公司 | Candesartan compound, preparation method and application thereof |
| WO2023075461A1 (en) * | 2021-10-27 | 2023-05-04 | 지용하 | Composite composition containing angiotensin receptor blocker and sglt2 inhibitor |
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| CN102482290B (en) * | 2010-08-10 | 2014-01-15 | 上海恒瑞医药有限公司 | C-aryl glucoside derivatives, preparation rpocess and pharmaceutical use thereof |
| CN104017031A (en) * | 2014-06-21 | 2014-09-03 | 李友香 | Hypoglycemic drug and composition |
| CN104780942A (en) * | 2012-08-30 | 2015-07-15 | 大正制药株式会社 | Combination of SGLT2 inhibitor and anti-hypertension drug |
| CN105939728A (en) * | 2014-01-31 | 2016-09-14 | 詹森药业有限公司 | Methods for the treatment and prevention of renal disorders and fatty liver disorders |
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2018
- 2018-11-19 CN CN201811373251.9A patent/CN109806397A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102482290B (en) * | 2010-08-10 | 2014-01-15 | 上海恒瑞医药有限公司 | C-aryl glucoside derivatives, preparation rpocess and pharmaceutical use thereof |
| CN104780942A (en) * | 2012-08-30 | 2015-07-15 | 大正制药株式会社 | Combination of SGLT2 inhibitor and anti-hypertension drug |
| CN105939728A (en) * | 2014-01-31 | 2016-09-14 | 詹森药业有限公司 | Methods for the treatment and prevention of renal disorders and fatty liver disorders |
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| ALI F. ABDEL-WAHAB ET AL.: ""Renal protective effect of SGLT2 inhibitor dapagliflozin alone and in combination with irbesartan in a rat model of diabetic nephropathy"", 《BIOMEDICINE & PHARMACOTHERAPY》 * |
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| 郑红志等主编: "《内分泌疾病诊断与治疗》", 30 September 2016, 吉林科学技术出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115894454A (en) * | 2021-09-06 | 2023-04-04 | 天地恒一制药股份有限公司 | Candesartan compound, preparation method and application thereof |
| WO2023075461A1 (en) * | 2021-10-27 | 2023-05-04 | 지용하 | Composite composition containing angiotensin receptor blocker and sglt2 inhibitor |
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