CN107043361A - Treat anginal compound, Preparation method and use - Google Patents

Treat anginal compound, Preparation method and use Download PDF

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Publication number
CN107043361A
CN107043361A CN201710379792.1A CN201710379792A CN107043361A CN 107043361 A CN107043361 A CN 107043361A CN 201710379792 A CN201710379792 A CN 201710379792A CN 107043361 A CN107043361 A CN 107043361A
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compound
pharmaceutically acceptable
acceptable salt
acid
preparation
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CN107043361B (en
Inventor
何广卫
李家明
储昭兴
许勤龙
赵炎
莫佳佳
林高峰
郭敬
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Hefei Enruite Pharmaceutical Co Ltd
HEFEI YIGONG MEDICINE CO Ltd
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Hefei Enruite Pharmaceutical Co Ltd
HEFEI YIGONG MEDICINE CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to medicinal chemistry art, specifically related to compound I, II, III legal persons Reynolds oxazine derivatives or its pharmaceutically acceptable salt, their preparation method, the Pharmaceutical composition containing these compounds and their medical usage, pharmacodynamic experiment proves that compound of the invention, which has, treats anginal effect.

Description

Treat anginal compound, Preparation method and use
Technical field
The present invention relates to medicinal chemistry art, and in particular to Reynolds oxazine derivatives or its pharmaceutically acceptable salt, they Preparation method, the Pharmaceutical composition containing these compounds and their medical usage, especially as treatment angina pectoris The purposes of medicine.
Background technology
Angina pectoris (anginapectoris) is the common sympton of coronary atherosclerotic heart disease, by cardiac muscle drastically , transient ischemic and anoxic cause cardiac blood, oxygen imbalance of supply and demand and cause.Raising, life side with living standards of the people The change of formula and the quickening of rhythm of life, the anginal incidence of disease increase year by year.Antianginal drug owner is clinically commonly used at present Have：NO donor medicines nitrate esters and nitrous acid ester, representing medicine has nitroglycerin, isoamyl nitrite.Nitroglycerin Occur nodal tachycardia, shock, acute myocardial infarction AMI, acute left heart failure, myocardial ischemia exacerbation often in Clinical practice Deng adverse reaction [Strait Pharmaceutical Journal .2005,17 (6):180-182.]；Beta-blocker, what is clinically commonly used has Mei Tuoluo You, Propranolol.Blood pressure reduction, block, decreased heart rate and the heart occur in clinical treatment angina pectoris for metoprolol Adverse reaction [the clinical rational drug use .2016,9 (4C) such as force failure exacerbation:172-173.]；Calcium ion channel blocker, at present There are the nifedipine of dihydropyridines and the Verapamil of non-dihydropyridines for clinical.Nifedipine clinical adverse Also increase increasingly, except adverse reactions such as headache, Blushing, tachycardias, new adverse reaction also when have been reported that [middle traditional Chinese medicines Industry .2010,19 (2):61-62.]；Fatty acid oxidation inhibitors, representing medicine has ranolazine, Trimetazidine.Ranolazine is being played Any change of haemodynamics will not be caused during Antianginal effect, but often cause constipation, it is nausea, headache, dizziness, tired Deng adverse reaction.Although antianginal drug species are various, drug effect is not good, side effect be still greatly it is clinical face it is main Problem.Therefore, find the new high activity of a class, low side effect antianginal drug it is still particularly significant.
The content of the invention
The invention discloses three Reynolds oxazine derivatives, pharmacodynamics test proves that compound of the invention is in angina pectoris side The effect in face is better than ranolazine, is expected to be applied to clinical treatment angina pectoris.
The structural formula of compound of the present invention is as follows：
According to the present invention, pharmaceutically acceptable salt includes compound I, II, III and following acid-addition salts：Hydrochloric acid, sulphur It is acid, hydrobromic acid, citric acid, butanedioic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, right Toluenesulfonic acid, forulic acid, malic acid, aspartic acid, glutamic acid.
The preparation method of the compound of the present invention is as follows：
Compound I preparation method includes：
Compound II preparation method includes：
Compound III preparation method includes：
Wherein a, b, c represent reaction condition.
a：DMF, butanone, THF may be selected in solvent, and sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, carbon may be selected in alkali
Potassium hydrogen phthalate, sodium methoxide, caustic alcohol, sodium hydrogen.
b：Ethanol, methanol, isopropanol, temperature may be selected in solvent：Room temperature~80 DEG C
c：Alkali may be selected:Sodium hydroxide, potassium hydroxide, solvent selection：Methanol/water, ethanol/water.
Here is the pharmacodynamics test and result of the compounds of this invention：
Extracting male Wistar rat, body weight 200-220g, adaptability raise 3 days, experiment before it is overnight fast on, be randomly divided into 6 groups, every group 8, relative medicine is given respectively, and (compound group gavage gives medicine 30mg/kg, and positive drug ranolazine gavage is given 30mg/kg is given, model group gives respective volume Vehicle controls, and normal group gives corresponding Vehicle controls), 90min each groups after administration Rats by intraperitoneal injection yellow Jackets 50mg/kg is anaesthetized.On subsequent each group (except blank control group) femoral venous catheter injection kidney Parathyrine 0.3ug/kg (removing normal group) induction ST-T ripples are raised, and electrocardiograph records 20min ECG, and measure gives adrenaline Amplitude (△ T) difference that is preceding and giving the ST ripples after adrenaline.△ T (ECG T wave changing value)=Injection of Adrenaline Electrocardiogram T wave heights (uv) before ECG T wave height (uv)-injection after 20min.
In addition, evaluating protective effect of the compound to cardiac muscle, anesthetized rat, abdominal aorta blood sampling, detection oxidative stress refers to Mark LDH, MDA, SOD, and stable angina pectoris pectoralgia index serum creatine kinase (CK-MB).
Experimental result is shown in Table 1, table 2.From Tables 1 and 2, compared with model group, each compound group and ranolazine group energy Inhibited adrenaline induced rat angina pectoris model ST-T ripples are raised (P ＜ 0.01)；Compared with ranolazine group, compound I Suppress adrenaline induced rat angina pectoris model ST-T ripples to raise with pole significant difference (P ＜ 0.01), compound II and III With significant difference (P ＜ 0.05).
Compared with model group, each compound group and ranolazine group can pole significantly reduce rat model serum MDA, LDH and the heart Injury of muscle characteristics index CK-MB content (P ＜ 0.01)；Compared with ranolazine, compound I can pole significantly reduce LDH, CK- MB content (P ＜ 0.01), significantly reduces MDA contents (P ＜ 0.05), and compound II can significantly reduce MDA contents (P ＜ 0.05), compound III can significantly reduce MDA, LDH, CK-MB content (P<0.05).
The influence (Mean ± SD, n=8) that the compounds on adrenal of table 1. element induced rat angina pectoris model ST-T ripples are raised
Note：▲P<0.05,▲▲P<0.01vs blank；△P<0.05,△△P<0.01vs models；*P<0.05, * * P<0.01vs thunders Promise piperazine
The influence (Mean ± SD, n=8) of the compounds on adrenal of table 2. element induced rat angina pectoris model blood biochemistry index
Note：▲P<0.05,▲▲P<0.01vs blank；△P<0.05,△△P<0.01vs models；*P<0.05, * * P<0.01vs thunders Promise piperazine
Pharmacology test result shows that the compounds of this invention can significantly inhibit raising for ST-T ripples, and the reduction stability heart is twisted The level of pain index serum creatine kinase, better than same reduction oxidative stress MDA and LDH level, positive control ranolazine. Therefore, compound of the invention can be used for treating the related disease of angina pectoris.
Anginal pharmaceutical composition is treated present invention also offers one kind, wherein the institute of the present invention containing therapeutically effective amount The compound or pharmaceutically acceptable salt and pharmaceutically acceptable carrier stated.Described pharmaceutical composition can be common Tablet or the conventional dosage form of the galenic pharmacy such as capsule, sustained release tablets, controlled release tablet, oral liquid, parenteral solution.
Embodiment
Embodiment 1
Compound I synthesis
The synthesis of 1- (4- methoxyl groups -2- (1- oxiranyhnethoxies) phenyl) -1- ethyl ketones
1- (2- hydroxyl -4- methoxyphenyls) -1- ethyl ketones (3.0g, 18.1mmol) are sequentially added in 100mL three-necked bottles, DMF (30mL), NaH (867.0mg, 21.7mmoL), are stirred 30 minutes.Under nitrogen protection, epoxychloropropane is added dropwise DMF (5mL) solution of (1.67 g, 18.1mmol), 60 DEG C of reactions are stayed overnight.Room temperature, plus 50mL water quenchings are cooled to after reaction completely Go out, ethyl acetate extraction (40mL × 3) merges organic phase, saturated common salt water washing (25mL × 3), anhydrous sodium sulfate drying, mistake Filter, concentration, through column chromatography (petroleum ether:Ethyl acetate=5:1) elution separation, be concentrated under reduced pressure to obtain 1- (4- methoxyl groups -2- (1- rings Oxygen ethyl methoxyl group) phenyl) -1- ethyl ketones, 1.58g, yield is 39.4%.
2- (4- (3- (2- acetyl group -5- methoxyphenoxies) -2- hydroxypropyls) piperazine -1- bases)-N- (2,6- dimethyl benzenes Base) acetamide (compound I) synthesis
Compound 2 (718.8mg, 3.23mmol), ethanol (20mL), N- (2,6- bis- are sequentially added in 100mL three-necked bottles Aminomethyl phenyl) -1- piperazineacetamides (800.0mg, 3.23mmoL).Room temperature reaction is stayed overnight.TLC display reactions are completed.Concentration is anti- Liquid is answered, through column chromatography (dichloromethane:Methanol=20:1) elution separation, be concentrated under reduced pressure to obtain white solid 1.1g (compound I), receives Rate is 72.4%.1H NMR(400MHz,DMSO-d6)δ:9.15 (s, 1H, NHCO), 7.68 (d, J=8.8Hz, 1H, ArH), 7.07 (brs, 3H, ArH), 6.55-6.69 (m, 2H, ArH), 4.93 (d, J=4.0Hz, 1H, CHOH), 4.14 (d, J=5.8 Hz,1H,CHCH2O),4.03-4.08(m,2H,CHCH2O),3.84(s,3H,OCH3),3.12(s,2H,COCH2), 2.52- 2.71(m,12H,PyH,NCH2and COCH3),2.47-2.42(m,1H,NCH2),2.15(s,6H,CH3).13C NMR (125MHz,DMSO-d6)δ:199.55,171.09,167.33,163.53,138.20,138.10,134.86,130.73, 129.46,123.50,109.13,102.11,74.82,69.44,64.54,64.19,58.71,56.43,56.22,35.20, 21.35. ESI-Mass for C26H35N3O5:m/z 470.31[M++H].
Embodiment 2
Compound II synthesis
The synthesis of 4- (benzyloxy)-m-methoxybenzaldehyde
Vanillic aldehyde (10g, 0.065mol), DMF (50mL), K are sequentially added in 100mL three-necked bottles2CO3(13.7g, 0.099mol), benzyl chloride (10g, 0.079mol) is added dropwise, is stirred overnight at room temperature, plus 50mL water quenchings are gone out, dichloromethane extraction (30mL × 3), merge organic phase, wash (25mL × 3), anhydrous sodium sulfate drying, and filtering, concentration, hexamethylene are recrystallized 12.45g, yield is 79.1%.
The synthesis of 3- (4- (benzyloxy) -3- methoxyphenyls) epoxy ethyl -2- methyl formates
Compound 4 (10g, 0.041mol), tetrahydrofuran (200mL), and epoxy chlorine are sequentially added in 500mL three-necked bottles Propane (15.2g, 0.165mol), at -10 DEG C, reaction solution is slowly dropped to by the methanol solution (7.7g, 50mL) of sodium methoxide In after, react at room temperature 4 hours, separate out solid.Suction filtration, solid obtains 3.2g with recrystallizing methanol, and yield is 24.8%.
The synthesis of 2- hydroxyls -3- (4- hydroxy 3-methoxybenzenes base) methyl propionate
Compound 5 (1g, 3.18mmol), methanol (120mL), rear addition to be dissolved are sequentially added in 250mL three-necked bottles Pd/C (0.1g), after reaction half an hour, filtering is eluted through column chromatography and separated, be concentrated under reduced pressure to obtain 680mg, and yield is 94.4%.
The synthesis of 2- (4- (3- chlorine-2-hydroxyls propyl group) piperazine -1- bases)-N- (2,6- 3,5-dimethylphenyls) acetamide
Compound 9 (2.0g, 8.09mmol) is dissolved in water (8mL), epoxychloropropane (748.2mg, 8.09 are added at room temperature mmol).2h is reacted at room temperature, TLC display reactions are completed.Plus 20mL water, ethyl acetate extraction (25mL × 3).Merge organic phase, nothing Aqueous sodium persulfate is dried, filtering, concentration, through column chromatography (dichloromethane:Methanol=40:1) elution separation, is concentrated to give 2.0g, yield For 72.8%.
1.9 3- (4- (3- (4- (2- ((2,6- 3,5-dimethylphenyls) amino) -2- oxoethyls) piperazine -1- bases) -2- hydroxyls Propoxyl group) -3- methoxyphenyls) -2 hydroxy propanoic acid methyl esters synthesis
Compound 10 (720.0mg, 2.12mmol) is dissolved in acetonitrile (20mL), at room temperature add compound 6 (527.2mg, 2.33mmoL) and K2CO3(585.6mg,4.24mmol).80 DEG C of reactions are stayed overnight.TLC display reactions are complete.Plus 20mL water, acetic acid Ethyl ester extracts (25mL × 4).Merge organic phase, anhydrous sodium sulfate drying, filtering, concentration, through column chromatography (dichloromethane:Methanol =25:1) 400.0mg, yield 35.7% are purified to obtain.
3- (4- (3- (4- (2- ((2,6- 3,5-dimethylphenyls) amino) -2- oxoethyls) piperazine -1- bases) third oxygen of -2- hydroxyls Base) -3- methoxyphenyls) -2- hydracrylic acids (compound II) synthesis
Compound 11 (400.0mg, 0.76mmol) is dissolved in methanol (15mL), 1N NaOH solutions (1.51 are added at room temperature mL,1.51mmol).React at room temperature 2h.TLC display reactions are complete.Concentration of reaction solution, plus 10mL water, ethyl acetate extraction (10mL ×2).Aqueous phase adjusts pH to 5-6 with 1N HCl solutions.Concentration of reaction solution, plus methanol (10mL) and ethyl acetate (10 mL), room Temperature stirring 10min.Filtering, concentration filtrate obtain white solid 360.0mg (compound II), and yield is 92.5%.1H-NMR (400MHz,METHANOL-d4)δ:7.12 (brs, 3H, ArH), 6.98 (d, J=1.5Hz, 1H, ArH), 6.81-6.93 (m, 2H,ArH),4.25-4.20(m,1H,CHOHCOOOH),4.10-4.17(m,1H,CH2CHOH),4.02-3.94(m,2H, CHCH2O),3.87(s,3H,OCH3),3.32(s,2H,COCH2),3.11-2.75(m,12H,PyH,NCH2and CH2CHOH), 2.24(s,6H,CH3).13C NMR(125MHz,DMSO-d6)δ:175.40,171.13,151.66,149.40, 138.20, 138.10,136.33,130.72,129.45,124.40,116.76,116.51,75.34,69.75,64.54,64.25, 58.55, 56.40,56.27,43.69,21.35.ESI-Mass for C27H37N3O7:m/z 516.31[M++H].
Embodiment 3
Compound III synthesis
The synthesis of 2- ((2- methoxyphenoxies) methyl) oxirane
2- metoxyphenols (1.24g, 10mmol), sodium hydroxide (0.55g, 13.7 are sequentially added in 100mL three-necked bottles Mmol), four butyl bromation amine (100mg, 1mmol), 30mL DMF and 12mL water, nitrogen protection, 50 DEG C of stirring 30min.Dropwise Epoxychloropropane (2.76g, 30mmol) is added dropwise, continues to react 1h.Substantially completely, concentration of reaction solution uses acetic acid for TLC displays reaction It is 7 to adjust pH, and ethyl acetate extraction, organic phase is dried, and concentration is eluted through column chromatography and separated, be concentrated under reduced pressure to obtain colorless oil as product 1.3g, yield is 72.2%.
1- (2- methoxyphenoxies) -3- (4- (2,3,4- trimethoxy benzyls) piperazine -1- bases) propan-2-ol (compound III synthesis)
3 (496mg, 1.87mmol), ranolazine (355mg, 1.87mmol), ethanol are sequentially added in 50mL three-necked bottles (10 mL).40 DEG C of reaction 12h, TLC display reactions substantially completely, are cooled to room temperature, concentration of reaction solution, through column chromatography elution point From be concentrated under reduced pressure to obtain faint yellow solid (compound III) 520mg, yield 62.3%.1H NMR(400MHz,CDCl3)δ:6.91 (d, J=8.4Hz, 2H, ArH), 6.88-6.79 (m, 4H, ArH), 6.56 (d, J=8.8Hz, 2H, ArH), 4.08-4.02 (m, 1H, CHOH),3.95-3.93(m,2H,OCH2CH),3.81(s,3H,OCH3),3.80(s,3H,OCH3),3.78(s,3H, OCH3),3.77(s,3H,OCH3),3.41(s,2H,NCH2),2.90-3.11(m,10H,PyH and NCH2CH)。

Claims (4)

1. the compound of following any structure or its pharmaceutically acceptable salt：
2. the compound of claim 1 or its pharmaceutically acceptable salt, described pharmaceutically acceptable salt is claim 1 Hydrochloride, sulfate, hydrobromate, citrate, succinate, tartrate, phosphate, lactate, the acetone of compound Hydrochlorate, acetate, maleate, mesylate, benzene sulfonate, tosilate, ferulate, aspartate or paddy ammonia Hydrochlorate.
3. a kind of pharmaceutical composition, wherein the compound containing claim 1 or its pharmaceutically acceptable salt and pharmaceutically may be used The carrier of receiving.
4. the compound of claim 1 or its pharmaceutically acceptable salt are used to prepare in prevention or treatment angina pectoris relevant disease Medicine purposes.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1404471A (en) * 2000-02-22 2003-03-19 Cv治疗公司 Substituted piperazine compounds
US20150166496A1 (en) * 2011-11-30 2015-06-18 Korea Institute Of Science And Technology Derivatives of 1-phenoxy propan-2-ol and pharmaceutical composition containing the same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1404471A (en) * 2000-02-22 2003-03-19 Cv治疗公司 Substituted piperazine compounds
US20150166496A1 (en) * 2011-11-30 2015-06-18 Korea Institute Of Science And Technology Derivatives of 1-phenoxy propan-2-ol and pharmaceutical composition containing the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
REGISTRY: "RN号为774128-84-6", 《STN》 *

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