CN102627613A - 2-[(4,6-dimethyl pyrimidine-2-)oxyl]-3-cyano-3,3-dibenzyl propionic acid optical isomer, its preparation method and medical application - Google Patents
2-[(4,6-dimethyl pyrimidine-2-)oxyl]-3-cyano-3,3-dibenzyl propionic acid optical isomer, its preparation method and medical application Download PDFInfo
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- CN102627613A CN102627613A CN2012100445434A CN201210044543A CN102627613A CN 102627613 A CN102627613 A CN 102627613A CN 2012100445434 A CN2012100445434 A CN 2012100445434A CN 201210044543 A CN201210044543 A CN 201210044543A CN 102627613 A CN102627613 A CN 102627613A
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- propionic acid
- dimethyl pyrimidine
- oxygen base
- itrile group
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- LJDUWESDCGAWAU-SFHVURJKSA-N C[C@@H](C(c1ccccc1)(c1ccccc1)C#N)Oc1nc(C)cc(C)n1 Chemical compound C[C@@H](C(c1ccccc1)(c1ccccc1)C#N)Oc1nc(C)cc(C)n1 LJDUWESDCGAWAU-SFHVURJKSA-N 0.000 description 1
- GNOYURORCNYORB-LJQANCHMSA-N Cc1cc(C)nc(O[C@@H](C(c2ccccc2)(c2ccccc2)C#N)C(O)=O)n1 Chemical compound Cc1cc(C)nc(O[C@@H](C(c2ccccc2)(c2ccccc2)C#N)C(O)=O)n1 GNOYURORCNYORB-LJQANCHMSA-N 0.000 description 1
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Abstract
The invention relates to an optically pure compound, a preparation method and its medical application, specifically to a 2-[(4, 6-dimethyl pyrimidine-2-)oxyl]-3-cyano-3,3-dibenzyl propionic acid optical isomer, its preparation method and a medical application.
Description
Technical field
The present invention relates to a kind of optical pure compound, preparation method and medicinal use thereof, specifically a kind of 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenyl-propionic acid optical isomer and preparation method thereof and medicinal use.
Background technology
(endothelin is the polypeptide of being made up of 21 amino acid by discoveries such as Yanagisawa in 1988 ET) to ET-1, belongs to sarafotoxin (sarafotoxin) family, has the very strong blood vessel function that contracts.Confirmed that at present endothelium have three kinds of ET-1, ET-2, ET-3.Mammals mainly contains two kinds of ET acceptor: ET
AAnd ET
B, being g protein coupled receptor, ET-1 is through its performance physiological action.ET
AThe acceptor overwhelming majority is distributed in VSMC, with the ET-1 selective binding, plays vasoconstriction and hyperplasia effect; ET
BAcceptor is nonselective, and is identical with the avidity of three kinds of ET isopeptides, and it mainly is distributed in endotheliocyte, plays vasorelaxation action through the release of inducing nitrogen protoxide (NO), but sub-fraction ET is also arranged
BAcceptor is present in some smooth muscle cell, plays the vasoconstriction effect.
ET has BA widely, makes it relevant with multiple diseases, such as hypertension, congestive heart failure, renal failure, pulmonary hypertension, metastatic prostate cancer, cerebral vasospasm etc.Generation or the antagonism of blocking-up ET-1 its with the combining of acceptor, can be used to treat above-mentioned disease.Research thinks that endothelin-receptor antagonists will become the newtype drug that is used to treat diseases such as hypertension, heart failure, subarachnoid hemorrhage, tumour, mellitus, ephrosis and renal failure, asthma clinically.
On June 15th, 2007, drugs approved by FDA the medicine An Beishengtan ambrisentan (commodity are called Letairis) of pulmonary hypertension of Gilead Science company.Ambrisentan is a kind of highly selective ET-1 ET that is used to treat pulmonary hypertension (PAH)
AReceptor antagonist belongs to β-diphenylprop acids, can imitate by force to suppress vasoconstriction due to the ET-1.
The applicant through the structure of modification to An Beishengtan, has obtained serial An Beishengtan analogue, through in-vitro screening; Obtain the strongest compound 2-of antagonistic activity [(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3, the 3-diphenyl-propionic acid; Almost suitable with An Beishengtan, can reach document (Bioorganic Medicinal Chemistry Letters referring to Chinese patent 201110043855.9 (application number); 2011,21:3894-3897).Melvin; JR. in patent WO 2009017777 A2, reported the correlative study of An Beishengtan metabolite; Research shows; 3 methoxyl groups of An Beishengtan become SA 3 substituted An Beishengtan of hydroxyl, thereby have shortened An Beishengtan action time in vivo in vivo very easily by metabolism.Compare with 3 methoxyl groups of An Beishengtan, our target compound 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3 of the 3-diphenyl-propionic acid is itrile group, be difficult for by metabolism in vivo, thereby maybe prolong drug action time.Because of 2-[(4; The oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3; Contain a chiral centre in the 3-diphenyl-propionic acid structure; And marketed drug An Beishengtan is the single optical isomer of S configuration, so we split two optical isomers that prepared it to it, and its two optical isomers made pharmacology activity research.The result finds; The endothelin-antagonist activity of S type optical isomer is far longer than R type optical isomer; With An Beishengtan suitable drug effect reaction is arranged; Comprehensive 3 itrile groups of aforesaid this compound are than the advantage of 3 methoxyl groups of An Beishengtan, and might become the endothelin antagonist that is superior to An Beishengtan future.
Summary of the invention
The applicant is with 2-[(4; The oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3; The racemic modification of 3-diphenyl-propionic acid splits separation; Obtain its S type (formula I) and R type (formula II) optical isomer, and respectively its activity is studied, find that the endothelin-antagonist activity of S type optical isomer is far longer than R type optical isomer.
The present invention aims to provide a kind of 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3, and 3-diphenyl-propionic acid S type optical isomer is to improve drug effect, reduce dosage, to reduce adverse reaction rate.Technical problem to be solved is the fractionation and the pharmacodynamics checking of S type and two kinds of optical isomers of R type.
The alleged 2-of the present invention [(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3, the single optical isomer of 3-diphenyl-propionic acid is the compound shown in the formula I.This compound can be pharmacy acceptable salt, hydrate or solvolyte.
In the present invention; Formula I and formula II optical pure compound are through with 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenyl-propionic acid racemic mixture and optical purity organic bases compounds salify and split; And through R type and S type salt different solubility and Crystallization Separation is come out in specific solvent; Again salt is obtained R type or S type optical purity 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenyl-propionic acid through simple acid-alkali treatment.
Specifically the preparation method of formula I optical pure compound is exactly 2-[(4; The oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3; The method for splitting of 3-diphenyl-propionic acid racemic modification comprises salify, separation, purifying, and its main idea is that racemic modification and optical purity organic bases compounds react in organic solvent and generate the salt deposition and split; Obtain formula I salt deposition or organic solution after the separation, with obtaining formula I compound behind salt or the solution purification.
Preferred (S)-(-) of described optical purity organic bases compounds-α-Ben Yian, (S)-(-)-1-(4-chloro-phenyl-) ethamine, (S)-(-)-1-(4-bromophenyl) ethamine.
The invention still further relates to can be from those compounds (prodrug) of the compound that wherein discharges general formula I, the ester and the acid amides of the acid that for example general formula I comprised.Preferred prodrug is mainly to discharge under the condition in some position of health such as stomach, intestines, circulation of blood, liver.
Another object of the present invention is to provide of the application of the compound of general formula I in diseases such as treatment hypertension, heart failure, subarachnoid hemorrhage, tumour, mellitus, ephrosis, asthma.
Description of drawings
Fig. 1 is that the racemic modification optical purity detects color atlas.
Fig. 2 is that S-isomer optical purity detects color atlas.
Fig. 3 is that R-isomer optical purity detects color atlas.
Embodiment
Specify content of the present invention through embodiment below.In the present invention, the embodiment of the following stated is in order better to set forth the present invention, is not to be used for limiting scope of the present invention.
S-2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3, the 3-diphenyl-propionic acid
In reaction flask, add 10g 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenyl-propionic acid racemic modification adds 200mL acetone again, is heated to backflow.Reflux state drips the mixed solution of 2.09g S-(-)-1-(4-chloro-phenyl-) ethamine and 50mL acetone down, adds back back flow reaction 30min.Put and be chilled to room temperature, have a large amount of white crystals to separate out, leach crystallization, S-2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3, the thick product 5.67g of 3-diphenyl-propionic acid-S-(-)-1-(4-chloro-phenyl-) ethylamine salt.
Above S-2-[(4; The oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3, the thick product 5.67g of 3-diphenyl-propionic acid-S-(-)-1-(4-chloro-phenyl-) ethylamine salt adds the dissolving that refluxes of 250mL acetone; Room temperature is placed and is spent the night; Separate out a large amount of white crystals, leach crystallization and be fractionation salt refining article, be weighed as 4.01g.
To make with extra care fractionation salt 4.01g and add the 4mL dissolve with methanol, add 10%H
2SO
4Be acidified to pH to 3, add 40mL water, separate out a large amount of depositions, suction filtration, filter cake in vacuum is dry, promptly gets S-2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenyl-propionic acid 2.83g.Yield 28.3%.
R-2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3, the 3-diphenyl-propionic acid
In reaction flask, add 10g 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenyl-propionic acid racemic modification adds 200mL acetone again, is heated to backflow.Reflux state drips the mixed solution of 2.09g R-(+)-1-(4-chloro-phenyl-) ethamine and 50mL acetone down, adds back back flow reaction 30min.Put and be chilled to room temperature, have a large amount of white crystals to separate out, leach crystallization, R-2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3, the thick product 5.52g of 3-diphenyl-propionic acid-R-(+)-1-(4-chloro-phenyl-) ethylamine salt.
Filtrating promptly is S-2-[(4; The oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenyl-propionic acid acetone soln is sloughed acetone and is promptly obtained the thick product of S-optical isomer; Perhaps in this acetone soln, add S-(-)-1-(4-chloro-phenyl-) ethamine acetone soln and carry out purifying, operation is with example 1.
Above R-2-[(4; The oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3, the thick product 5.52g of 3-diphenyl-propionic acid-R-(+)-1-(4-chloro-phenyl-) ethylamine salt adds the dissolving that refluxes of 250mL acetone; Room temperature is placed and is spent the night; Separate out a large amount of white crystals, leach crystallization and be fractionation salt refining article, be weighed as 3.97g.
To make with extra care fractionation salt 3.97g and add the 4mL dissolve with methanol, add 10%H
2SO
4Be acidified to pH to 3, add 40mL water, separate out a large amount of depositions, suction filtration, filter cake in vacuum is dry, promptly gets R-2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenyl-propionic acid 2.80g.Yield 28.0%.
R type, S type and racemic modification 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3, the HPLC of 3-diphenyl-propionic acid optical purity measures
HPLC model: Agilent 1100 highly effective liquid phase chromatographic systems (comprising automatic sampler, VWD detector, Agilent chromatographic working station).
Chromatographic column: Chiralpak IC, 5um, 4.6*250mm;
Moving phase: normal hexane: Virahol: trifluoroacetic acid=75: 25: 0.1;
Column temperature: 25 ℃;
Detector: ultraviolet, 211nm;
Flow velocity: 0.5mL/min.
Through detecting, 1,2 of instances are S types and the R type 2-of preparation [(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3 respectively, and 3-diphenyl-propionic acid optical purity all reaches more than 99%, carries out chromatographic peak location and separating size checking with the racemic modification sample in the test.
Racemic modification body analytical results table (Fig. 1)
S-isomer analytical results table (Fig. 2)
R-isomer analytical results table (Fig. 3)
Embodiment 4
R type, S type and racemic modification 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenyl-propionic acid endothelin-antagonist activity determination experiment
Blind sieve is adopted in this experiment, and compound renumbers as follows,
A1:S type 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3, the 3-diphenyl-propionic acid
A2:R type 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3, the 3-diphenyl-propionic acid
A3:2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenyl-propionic acid racemic modification
A4: An Beishengtan
Normal rabbits auricular vein pneumatic needl is opened chest after putting to death, and takes out thoracic aorta, separates.Place 4 ℃ of cold K-H liquid that contain saturated oxygen to remove reticular tissue.Rub gently with cotton swab and to remove the endarterium epithelial cell, be cut into the vascular circle of 4-6mm, suspension contains in the 8ml bath of K-H buffer salt solution, logical pure O
2PH7.4,37 ℃ of constant temperature.The adjusting rest tension is 2g, balance 60min.Add 10
-6MolL
-1Sympathin (NA) rises vascular circle tension force, adds 10 again
-6MolL
-1Vagusstoff (Ach) is through vasodilative degree check endothelium integrity.If the diastole amplitude reaches 50% after adding Ach, it is complete then to be regarded as endothelium, does not produce diastole or diastole amplitude less than 5%, then is regarded as the endothelium-denuded success.
Add ET-1 (10
-8MolL
-1Final concentration), hatch 40min when treating that vasoconstriction reaches maximum tension, the administration group adds test-compound A1-A4 (10 respectively
-7MolL
-1Final concentration), establishing the solvent group is control group.Observe behind the 40min it to the antagonistic action of the vasoconstriction reaction of ET-1 and write down the vascular circle shrink tension.
The calculating of endothelin antagonist inhibiting rate: ET-1 the tension force during to vasoconstriction 40min be A (g), test-compound (10
-6MolL
-1Final concentration) hatch that vasoconstriction tension force is B (g) behind the 40min, then its to suppress percentage be (A-B)/A * 100%.
The pharmacology table with test results
A1 (10
-7) inhibiting rate: 43.27%, A2 (10
-7) inhibiting rate: 10.58%, A3 (10
-7) inhibiting rate: 20.27%, A4 (10
-7) inhibiting rate: 49.34%.
Can find out S type 2-[(4 by above data; The oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3; 3-diphenyl-propionic acid (A1) and An Beishengtan (A4) have the reaction of suitable drug effect, and its ET-1 antagonistic validity response is R type 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3; Mostly 4 times of 3-diphenyl-propionic acid (A2) are more than 2 times of racemic modification (A3).
More than be to explanation of the present invention, still, the present invention is not limited in specific embodiments as herein described, but has comprised that interior all of accompanying claims scope change form.
Claims (10)
1. a 2-[(4, the oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenyl-propionic acid optical isomer, its chemical structure is suc as formula shown in the I:
2. the pharmacy acceptable salt of the said optical isomer of claim 1, hydrate or solvolyte.
3. the preparation method of the described optical isomer of claim 1; Be the method for splitting of its racemic modification, comprise salify, separation and purifying, it is characterized in that: described salify is that racemic modification and optical purity organic bases compounds react living salt deposition and split in organic solvent; Separate and obtain S-2-[(4; The oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenylprop hydrochlorate deposition or its solution obtain S-2-[(4 after purified; The oxygen base of 6-dimethyl pyrimidine-2-)]-3-itrile group-3,3-diphenyl-propionic acid optical isomer.
4. preparation method according to claim 3, preferred (S)-(-) of described optical purity organic bases compounds-α-Ben Yian, (S)-(-)-1-(4-chloro-phenyl-) ethamine, (S)-(-)-1-(4-bromophenyl) ethamine.
5. claim 1 or 2 described optical isomers are as the application of endothelin-receptor antagonists.
6. claim 1 or 2 described optical isomers are used for the application that there is the medicine of the disease that level of ET raises in production for treating.
Claim 1 or 2 described optical isomers be used for production for treating by ET-1 cause its produce with or the application of the medicine of the disease of development.
8. claim 1 or 2 described optical isomers are used for the application of chronic heart failure, restenosis, hypertension, pulmonary hypertension, acute/chronic kidney hypofunction, cerebral ischaemia, asthma, benign prostatic hyperplasia and prostate cancer.
9. claim 1 or 2 described optical isomers and one or more are selected from the combination of activeconstituents such as renin inhibitor, Angiotensin II antagonist, angiotensin-converting enzyme (ACE) suppressor factor, the medium-sized endopeptidase of blended ACE/ (NEP) suppressor factor, Beta receptor blockers, diuretic(s), calcium channel blocker and the VEGF blocking-up material of renin-angiotensin inhibitor system.
10. oral a, enteron aisle outer or intraperitoneal applied agents and conventional pharmaceutical vehicle.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1222146A (en) * | 1996-04-12 | 1999-07-07 | Basf公司 | Novel 'alpha,-hydroxylic acid derivatives, their prodn. and use |
| WO2010091877A2 (en) * | 2009-02-13 | 2010-08-19 | Ratiopharm Gmbh | Process for producing ambrisentan |
| CN102161643A (en) * | 2011-02-24 | 2011-08-24 | 中国药科大学 | Heterocyclic carboxylic acid derivative and application as endothelin receptor antagonist thereof |
-
2012
- 2012-02-27 CN CN2012100445434A patent/CN102627613A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1222146A (en) * | 1996-04-12 | 1999-07-07 | Basf公司 | Novel 'alpha,-hydroxylic acid derivatives, their prodn. and use |
| WO2010091877A2 (en) * | 2009-02-13 | 2010-08-19 | Ratiopharm Gmbh | Process for producing ambrisentan |
| CN102161643A (en) * | 2011-02-24 | 2011-08-24 | 中国药科大学 | Heterocyclic carboxylic acid derivative and application as endothelin receptor antagonist thereof |
Non-Patent Citations (1)
| Title |
|---|
| JUN XIA: "Synthesis and in vitro evaluation of ambrisentan analogues as potential", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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Application publication date: 20120808 |