CN108299397B - A kind of active medicine and preparation method thereof for blood pressure lowering - Google Patents
A kind of active medicine and preparation method thereof for blood pressure lowering Download PDFInfo
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- CN108299397B CN108299397B CN201810234007.8A CN201810234007A CN108299397B CN 108299397 B CN108299397 B CN 108299397B CN 201810234007 A CN201810234007 A CN 201810234007A CN 108299397 B CN108299397 B CN 108299397B
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- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 102000056252 human ACE Human genes 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
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- 239000000902 placebo Substances 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- 230000002335 preservative effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of active medicine for blood pressure lowering, the drug is angiotensin converting enzyme inhibitor, and the invention further relates to the preparation methods of the drug.In vitro test the result shows that, the compounds of this invention for ACE have good inhibitory activity, IC50In 100nm or less.Animal experiment shows that the compounds of this invention has apparent hypotensive activity for spontaneous hypertensive rat, and antihypertensive effect is roughly the same with nitrendipine.
Description
Technical field
The present invention relates to drug fields, and particularly, the present invention relates to a kind of active medicine for blood pressure lowering, the drugs
For angiotensin converting enzyme inhibitor, the invention further relates to the preparation methods of the drug.
Background technique
Hypertension is the most common cardiovascular disease in China, and incidence is up to 20% in adult, hypertensive patient
Since arterial pressure is higher than normal arterial pressure for a long time, headache, dizzy, cardio palmus shape can not only be caused, and can cause patient's heart,
The organ injuries such as brain, kidney lead to hemorrhagic apoplexy, myocardial infarction, heart failure and cerebral thrombosis complication, make patient's hemiplegia or
It is dead, hence it is evident that reduce patients ' life quality.The drug of current common treatment hypertension has following six kinds: diuretics (may draw
Rise hypokalemia, influence glycometabolism, decline sugar tolerance), beta-Blocking agent (can bring central nervous system, digestive system and
The adverse reaction of vascular system), α-blockers, calcium antagonist (will lead to oedema, headache, flush, diuresis, low blood pressure and the heart
Dirty conduction is obstructed), angiotensin-ii receptor retarding agent (can cause dry cough, blood potassium height, even angioedema) and blood vessel are tight
Open plain converting enzyme inhibitor (ACEI).
ACEI has many advantages, such as: it has the function of decompression, has the function of cardioprotection, the work with protection kidney
With, adverse reaction is few, therefore be suitable for treatment various types hypertension, it is especially suitable especially suitable for accelerated hypertension
With the hypertensive patient of hyperlipidemia, diabetes and coronary heart disease.
The ACEI class drug listed at present is more than 30 kinds, such as captopril (captopril), zofenopril
(zofenopril), alacepril (alacepril), enalapril (enalapril), lisinopril (lidinopril), uncommon
Draw Puli (cilazapril), Ramipril (ramipril), benazepil (benazepril), quinapril
(quinapril), fosinopril (fosinpril) etc..They with ACE bond strength, bioavilability, half-life period, in vivo
Distribution etc. is each different.Although ACEI is various to have the advantages that, as antihypertensive effect is good and lasting, therapeutic domain
Extensively, Small side effects, but there are still some negative effects, after taking such as some patients, dry cough, asthma and marrow suppression occur
The adverse reactions such as system, angioneurotic edema, itch and Oncocytosis.How to find and synthesize outstanding ACEI is to grind
Study carefully the active area of hypotensor.
Summary of the invention
One aspect of the present invention is related to a kind of compound of formula I or its pharmaceutically acceptable salt, prodrug, solvate and packet
Include the stereoisomer including its various scalemic thereof:
Wherein:
R1、R2、R3、R4Selected from hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-C4 alkyl, C1-4 alkoxy, C1-4 alkane
Base amino, C1-4 alkoxy carbonyl group or C1-4 alkyl-carbonyl；
R5、R6Selected from hydrogen, halogen, C1-C4 alkyl or R5、R6It is formed together carbonyl；
Cy indicates heterocycle, is optionally selected from halogen, hydroxyl, cyano, nitro, amino, C1-C4 alkane by one or more
The group substitution of base, C1-4 alkoxy, C1-4 alkyl amino, C1-4 alkoxy carbonyl group or C1-4 alkyl-carbonyl；
L indicates C1-C8 alkylidene, optionally by one or more selected from halogen, hydroxyl, amino, C1-4 alkoxy
Group replaces；
M1、M2Selected from N or CR；
R indicate hydrogen, halogen, hydroxyl, cyano, nitro, amino, C1-C4 alkyl, C1-4 alkoxy, C1-4 alkyl amino or
C1-4 alkyl-carbonyl；
Wherein, the C1-C4 alkyl, C1-4 alkoxy, C1-4 alkyl amino, C1-4 alkoxy carbonyl group or C1-4 alkyl-carbonyl
In C1-C4 alkyl optionally by it is one or more selected from halogen, hydroxyl, amino, C1-2 alkoxy groups replace.
In one embodiment of the invention, the R1、R2、R3、R4Preferably hydrogen, halogen, hydroxyl, cyano, nitro or
C1-C4 alkyl.
In one embodiment of the invention, the R5、R6Preferably hydrogen or C1-C4 alkyl or R5、R6Shape together
At carbonyl.
In one embodiment of the invention, the Cy is preferably pyridyl group, thienyl, pyrrole radicals, pyrimidine radicals, thiazole
Base, pyrrolidinyl or piperidyl.
In one embodiment of the invention, the L is preferably-CH2-、-CH2CH2-、-CH2CH2CH2Or-CH2CH
(OH)CH2-。
In one embodiment of the invention, the M1、M2Preferably N or CH.
In one embodiment of the invention, the compound is selected from:
In the present invention, term halogen indicates fluorine, chlorine, bromine or iodine.
In the present invention, the carbon number of term Alkyl means straight shape or branch's chain state is the alkyl of 1-4, for example, methyl, ethyl,
N-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl.
In the present invention, (1) or (2) below term heterocycle basis representation:
(1) ring group is condensed with 1-4 heteroatomic five or hexa-atomic aromatic ring yls selected from N, O and S or their benzene,
When the ring member nitrogen atoms are N or S, described N, S can form oxide.For example, pyrrole radicals, indyl, furan can be enumerated
Mutter base, benzofuranyl, thienyl, benzothienyl, thiazolyl, benzothiazolyl, imidazole radicals, benzimidazolyl, triazole, four
Azoles, pyridyl group, pyrazolyl, pyrimidine radicals, pyrazinyl, triazine radical etc..
(2) saturation ring group or their benzene fused rings with a heteroatomic four selected from N, O and S of 1-4 to octatomic ring
Base, when the ring member nitrogen atoms are N or S, described N, S can form oxide.For example, can enumerate piperidyl, piperazinyl,
Equal piperazinyl, morpholinyl, thio-morpholinyl, pyrrolidinyl, pyrrolidinyl, tetrahydrofuran base, tetrahydro-thienyl, pyrazolidinyl.
Term " pharmaceutically acceptable salt " refers to the pharmaceutically acceptable organic or inorganic salt of the compounds of this invention.Show
Example property salt include sulfate, acetate, oxalates, chloride, bromide, iodide, nitrate, isonicotinic acid salt, lactate,
Salicylate, succinate, maleate, fumarate, formates and mesylate etc..
The compounds of this invention can be used as prodrug form and be given.Therefore, itself may have seldom pharmacological activity
Or certain derivatives without pharmacological activity are converted into when being administered on internal or body for example, by hydrolytic rupture
With required active the compound of the present invention.This derivative is referred to as " pro-drug ".
Solvate refers to the conjugate or complex compound of the compounds of this invention and one or more solvent molecules.Form solvent
Close object solvent example include but is not limited to water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and
Ethanol amine.
The compounds of this invention can exist in the form of isomers and its mixture；Such as tautomer, optics are different
Structure body, enantiomter, diastereoisomer.The compounds of this invention can be for example comprising asymmetric carbon atom, and therefore can be with
Enantiomer or diastereomer and its form of mixture exist, such as in the form of racemate.Chemical combination of the present invention
Object can exist with (R)-, (S)-or (R, S)-configuration, be (R)-or (S)-configuration preferably on the specific position of compound.
The invention also discloses the methods of 1 compound of preparation formula, can carry out according to route below and step:
(1) Formula II compound step 1: is reacted into production IV chemical combination with isocyanate ester compound shown in formula III
Object；
(2) step 2: formula IV compound is reacted with azole compounds shown in Formula V and generates compound of formula I；
Wherein, R1-R6、L、Cy、M1、M2Definition it is as described herein, X indicates halogen, preferably chlorine, bromine or iodine.
Another aspect provides a kind of pharmaceutical composition, comprising one or more compound of formula I or
Its pharmaceutically acceptable salt, prodrug, solvate and the stereoisomer including its various scalemic thereof, and
Pharmaceutically acceptable carrier, diluent, excipient or their combination.
The present invention can apply compound with any convenient form of medication, for example, tablet, powder, capsule, solution, outstanding
Supernatant liquid, syrup, spray, suppository, gel, emulsion, patch etc..Such composition can conventional group containing pharmaceutical preparation
Point, such as carrier, diluent, excipient, pH adjusting agent, sweetener, filler and other activating agents.If necessary to parenterally give
Medicine, composition are sterile, and are the solution or suspension form for being suitble to injection or infusion.
Typical composition is prepared by mixing the compounds of this invention and carrier, diluent or excipient.It is suitable for
Carrier, diluent or excipient can enumerate such as: carbohydrate, wax class, water soluble or expandable polymer, hydrophily or
Hydrophobic material, penetrating judgment, oils, solvent, water etc..Specific carrier, diluent or excipient used will depend on the present inventionization
Close mode and purpose that object is applied.It specifically may include for example: water, lactose, the right side as above-mentioned carrier, excipient and diluent
Revolve sugar, fructose, sucrose, D-sorbite, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gelatin, alginate, silicic acid
Calcium, calcium phosphate, cellulose, syrup, methylcellulose, polyvinylpyrrolidone, para hydroxybenzene sorb acid alkyl ester, talcum,
Magnesium stearate, stearic acid, glycerol, sesame oil, olive oil, soybean oil etc..
The composition can also include one or more kinds of buffers, solubilizer, surfactant, wetting agent, profit
Lubrication prescription, emulsifier, suspension, preservative, antioxidant, opacifier, glidant, colorant, sweetener, aromatic, flavoring agent and
Other known additive.
For adult patient, the compound of the present invention can will be as 1 administered dose in oral or non-oral mode
0.001~500mg, 1 day 1 time or be divided into and giving for several times.It should be noted that the administered dose can be according to the disease for the treatment of object
Type, the age of patient, weight, symptom etc. suitably increase and decrease.
The compound of the present invention can be used alone, or be used in combination with other therapeutic agents.Combination therapy can provide
Synergistic effect, i.e., the effect reached when active constituent is used together, greater than respectively using effect produced by the compound
Adduction.
The combination therapy can be applied with scheme concurrently or consecutively.When continuous administration, the combination can be with two
Kind or a variety of usages apply.Compound can be applied in single pharmaceutical composition together again or separate administration, and ought separately apply
Used time can carry out in succession simultaneously or with any order.
Another aspect provides the compound of formula I or its pharmaceutically acceptable salt, prodrug, solvations
Object and the purposes of stereoisomer in medicine preparation including its various scalemic thereof, the drug is for preventing
Or treatment hypertension.
Another aspect provides the compound of formula I or its pharmaceutically acceptable salt, prodrug, solvations
Object and the stereoisomer including its various scalemic thereof are preparing the use in angiotensin converting enzyme inhibitor
On the way.
Another aspect provides the compound of formula I or its pharmaceutically acceptable salt, prodrug, solvations
Object and the stereoisomer including its various scalemic thereof are preparing the purposes in hypotensive agent.
In vitro test the result shows that, the compounds of this invention for ACE have good inhibitory activity, IC50In 100nm
Below.Animal experiment shows that the compounds of this invention has apparent hypotensive activity, decompression for spontaneous hypertensive rat
Effect is roughly the same with nitrendipine.
Specific embodiment
The present invention is described below in more detail to facilitate the understanding of the present invention.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps
Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention
Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention
It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention
, or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is suitable for the preparation of other compounds of the invention.
- 1 (2H)-formyl of embodiment 1:2- ((1H- imidazoles -1- base) methyl)-N- (pyridin-4-yl) -3,4- dihydroquinoline
The synthesis of amine (compound 1)
2- chloromethyl -1,2 is taken, during 3,4- tetrahydroquinoline 10mmol are dissolved in the methylene chloride of 100ml, equivalent is added
4- isocvanato-pyridin, be stirred at room temperature 12 hours.Then methylene chloride dilute reaction solution is added, adds 2M hydrochloric acid
100ml, organic layer are washed with 2M HCl, saturated sodium bicarbonate washing, and saturated sodium-chloride washing is finally dry with anhydrous sodium sulfate
It is dry, solvent is removed under reduced pressure, vacuum drying obtains crude product, direct plunges into react in next step without further purification.
The product of above-mentioned drying is dissolved in 120ml THF, the NaOH aqueous solution 20ml of 20mmol is added, then drips again
Add 10mmol imidazoles to be dissolved in the solution in 20ml THF, is warming up to return stirring 6h.Solvent is removed under reduced pressure, toluene 100ml is added
Dissolution, is then washed with saturated sodium bicarbonate, saturated sodium-chloride washing, finally dry with anhydrous sodium sulfate, and solvent is removed under reduced pressure,
Residue is separated with silica gel column chromatography, using ethyl acetate/petroleum ether (1/5) as eluant, eluent, is finally separating to obtain target product
2.52g, two step total recoverys 76.4%.
Mass spectrum (ESI): 334 [M+H]+
Hydrogen composes (400MHz, CDCl3)δ8.93(s,1H),8.53(d,2H),7.95(s,1H),7.15-7.34(m,6H),
6.83(d,1H),6.72(d,1H),4.03(d,2H),3.63(m,1H),2.84(t,2H),1.94(m,2H)。
Embodiment 2:2- (2- hydroxyl -3- (1H- imidazoles -1- base) propyl)-N- (pyridin-4-yl) -3,4- dihydroquinoline -1
The synthesis of (2H)-formamide (compound 2)
The chloro- 3- of 1- (1,2,3,4- tetrahydroquinoline -2- base) propane -2- alcohol 10mmol is taken to be dissolved in the methylene chloride of 100ml
In in, the 4- isocvanato-pyridin of equivalent is added, is stirred at room temperature 10 hours.Then methylene chloride dilute reaction solution is added,
2M hydrochloric acid 100ml is added, organic layer is washed with 2M HCl, saturated sodium bicarbonate washing, and nothing is finally used in saturated sodium-chloride washing
Aqueous sodium persulfate is dry, and solvent is removed under reduced pressure, and vacuum drying obtains crude product, direct plunges into react in next step without further purification.
The product of above-mentioned drying is dissolved in 100ml ethyl alcohol, the NaOH aqueous solution 20ml of 20mmol is added, then drips again
Add 10mmol imidazoles to be dissolved in the solution in 20ml ethyl alcohol, is warming up to return stirring 8h.Solvent is removed under reduced pressure, toluene 100ml is added
Dissolution, is then washed with saturated sodium bicarbonate, saturated sodium-chloride washing, finally dry with anhydrous sodium sulfate, and solvent is removed under reduced pressure,
Residue is separated with silica gel column chromatography, using ethyl acetate/hexamethylene (1/8) as eluant, eluent, is finally separating to obtain target product
2.60g, two step total recoverys 68.9%.
Mass spectrum (ESI): 378 [M+H]+
Hydrogen composes (400MHz, CDCl3)δ8.92(s,1H),8.54(d,2H),7.96(s,1H),7.18-7.33(m,6H),
6.83(d,1H),6.73(d,1H),4.83(s,1H),4.13(d,2H),3.59(m,1H),3.24(m,1H),2.89(t,2H),
1.92(m,2H),1.65(m,2H)。
According to the similar method of embodiment 1, following compound is synthesized:
The external inhibitory activity of testing example 1:ACE
Using analyzed in vitro as described below measurement compound to the inhibitory activity of mankind ACE.
Recombinant human ACE is commercial goods (A Di system (R&D Systems), Minneapolis
(Minneapolis), MN, catalog number are respectively 929-ZN).Use fluorescent peptide substrate Mca-B K2 (Mca-Arg-Pro-
Pro-Gly-Phe-Ser-Ala-Phe-Lys(Dnp)-OH；Johnson (Johnson) et al. (2000) analytical biochemistry
(Anal.Biochem.) 286:112-118) (coming from Anna Bake (Anaspec), San Jose (San Jose), CA).
It is slow in analysis with 10 μM of concentration using corresponding fluorescent peptide at room temperature in the White-opalescent plate of the hole 384-
Electuary (50mM Tris/HCL at 25 DEG C, 100mM NaCl, 0.01% tween (Tween) -20,1 μM of Zn, 0.025%BSA)
Middle implementation analysis.Mankind ACE is that can make at room temperature in the concentration for obtaining 5 μM of Mca-BK2 Quantitative Westerns enzymatic hydrolysis in 20 minutes
With.
By the way that 12 concentration, (10 μM to 20pM) of 12.5 μ L, which are tested in compound, to be added 25 μ L enzymes and start to analyze.Make
Inhibitor with enzyme equilibrium 10 minutes, add 12.5 μ L fluorogenic substrates then to start the reaction.By cultivating after twenty minutes
10 μ L, 3.6% glacial acetic acid is added to terminate reaction.320nm is respectively set as in excitation wavelength and launch wavelength by fluorimeter
Plate is read when with 405nm.
According to the average high scale (unrestraint, 100% enzymatic activity) used when Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe and it is averaged low scale (completely
Inhibit, highest inhibitor concentration, 0% enzymatic activity) initial data (relative fluorescence unit) is normalized to % activity.Use unit
Point competitive model (lattice pressgang Pa De software company, Santiago, CA) implements the nonlinear regression of normalization data.By datagram
Accusing is IC50Value.As a result remember in following table 1:
External inhibitory activity of 1 compound of table to ACE
Test result shows that the compounds of this invention has good inhibitory activity for ACE, therefore can be used as depressor,
For preventing and treating hypertension.
Testing example 2: antihypertensive effect research
Measurement compound is tried to the antihypertensive effect of spontaneous high pressure pressure rat (SHR) using animal as described below
By 40 week old, 250-300 grams of weight of male SHR (Beijing Vital River Experimental Animals Technology Co., Ltd.) totally 72
Only, 12 groups are randomly divided into, every group of 6 animals, respectively negative control group (0.5%CMC-Na), positive controls (Ni Qundi
It is flat) and compound 1-10 group (all compounds are prepared in 0.5%CMC-Na), wherein positive controls and compound
1-10 is administered with the dosage of 2mg/Kg；Negative control is given only placebo.It is measured with tail sleeve method (BP2010A non-invasive blood pressure instrument)
Rat administration before, after gastric infusion 1h blood pressure, survey be averaged three times respectively, and result is subjected to statistical procedures.As a result
Remember in following table 2:
Antihypertensive effect (n=6) of 2 compound of table to spontaneous high pressure pressure rat
Test result shows that the compounds of this invention has apparent hypotensive activity for spontaneous hypertensive rat,
Antihypertensive effect is roughly the same with nitrendipine.
The foregoing describe the preferred embodiment for the present invention, and however, it is not to limit the invention.Those skilled in the art couple
Embodiment disclosed herein can carry out the improvements and changes without departing from scope and spirit.
Claims (7)
1. a kind of compound of formula I or its pharmaceutically acceptable salt and the alloisomerism including its various scalemic thereof
Body:
Wherein:
R1、R2、R3、R4Selected from hydrogen, hydroxyl, cyano, nitro or C1-C4 alkyl；
R5、R6Selected from hydrogen or R5、R6It is formed together carbonyl；
Cy indicates pyridyl group, thienyl, pyrrole radicals, pyrimidine radicals, thiazolyl, pyrrolidinyl or piperidyl, optionally by one or
More groups for being selected from C1-C4 alkyl replace；
L expression-CH2-、-CH2CH2-、-CH2CH2CH2Or-CH2CH(OH)CH2-；
M1、M2Selected from N or CR；
R indicates hydrogen.
2. compound according to claim 1, which is characterized in that the compound is selected from:
3. the preparation method of compound of formula I according to claim 1 comprising following steps:
(1) Formula II compound step 1: is reacted into production IV compound with isocyanate ester compound shown in formula III；
(2) step 2: formula IV compound is reacted with azole compounds shown in Formula V and generates compound of formula I；
Wherein, R1-R6、L、Cy、M1、M2Definition as described in the appended claim 1, X indicate halogen.
4. preparation method according to claim 3, which is characterized in that X indicates chlorine, bromine or iodine.
5. a kind of pharmaceutical composition, comprising one or more compound of formula I according to claim 1 or its can pharmaceutically connect
The salt received and stereoisomer and pharmaceutically acceptable carrier, excipient including its various scalemic thereof
Or their combination.
6. compound of formula I according to claim 1 or its pharmaceutically acceptable salt and being mixed including its various ratio
The purposes of stereoisomer in medicine preparation including object, the drug is for preventing or treating hypertension.
7. compound of formula I according to claim 1 or its pharmaceutically acceptable salt and being mixed including its various ratio
Stereoisomer including object is preparing the purposes in angiotensin converting enzyme inhibitor or hypotensive agent.
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| US4855291A (en) * | 1984-08-15 | 1989-08-08 | The Boots Company Plc | 1,4dihydroquinoline-3-carboxamides |
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| WO2009005002A1 (en) * | 2007-06-29 | 2009-01-08 | Dainippon Sumitomo Pharma Co., Ltd. | Quinolone derivative |
| WO2015150995A1 (en) * | 2014-04-04 | 2015-10-08 | Pfizer Inc. | Bicyclic-fused heteroaryl or aryl compounds and their use as irak4 inhibitors |
| WO2017025849A1 (en) * | 2015-08-13 | 2017-02-16 | Pfizer Inc. | Bicyclic-fused heteroaryl or aryl compounds |
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2018
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US3983121A (en) * | 1974-07-01 | 1976-09-28 | Council Of Scientific And Industrial Research | 1-Substituted 4-(β-2-quinolylethyl)piperazines and 1,2,3,4-tetrahydroquinolyl-ethyl analogues thereof |
| US4855291A (en) * | 1984-08-15 | 1989-08-08 | The Boots Company Plc | 1,4dihydroquinoline-3-carboxamides |
| CN1564820A (en) * | 2001-10-05 | 2005-01-12 | 瑞蔻达蒂股份有限公司 | Heterocyclic compounds for use in the treatment of disorders of the urinary tract |
| WO2008136457A1 (en) * | 2007-04-27 | 2008-11-13 | Dainippon Sumitomo Pharma Co., Ltd. | Nitrogen-containing aromatic derivative |
| WO2009005002A1 (en) * | 2007-06-29 | 2009-01-08 | Dainippon Sumitomo Pharma Co., Ltd. | Quinolone derivative |
| WO2015150995A1 (en) * | 2014-04-04 | 2015-10-08 | Pfizer Inc. | Bicyclic-fused heteroaryl or aryl compounds and their use as irak4 inhibitors |
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