TW407141B - Vasomolol, an ultra short-acting and vasodilatory vanilloid type <beta>1- adrenoceptor antagonist - Google Patents

Abstract

This invention is related to novel vasomolol, compounds of this invention have the following formula wherein R1 represents hydrogen, C 1-4 alkyl group. Vasomolol is an ultra short acting and vasodilatory selective <beta> 1-adrenoceptor antagonist, and is devoid of ISA.

Description

407141 A7 B7, V. Description of the invention () 1. Isoproterenol (is〇Proteren〇l) 2. Propranolol 3. Vasomolol 4. Esmolol chart ( 7) Effect of radioactive substance binding (8) Competition curve of ventricular membrane binding position 1. propranolol 2. Wsoraolol 3. esmolol Figure (9) 呱 索默 （ vasomolol) compound synthesis method Example 1 Slowly add vanadium vanillin (van i 11 i η) 30% sodium hydroxide to 15.2 grams of I ϋ. 丨 Moore until it is completely dissolved and becomes dirty, add, etc. Molar number Sodium hydroxide is wrapped on the outside of the reaction bottle with ice cubes to control the temperature below 25 ° C, and then 5 times the molar amount of epichloric acid (epi-.111010: 〇1 ^ (11 ^ 116), 3 times the molar amount of tert-butylamine (161: 1; -1) 11171 &amp; 11 ^ 116), after refluxing at 55 ° C for 2 hours, the reaction solution was taken out and concentrated under reduced pressure, and dichloromethane Crystallization of methane gives 3 · -methoxy-4 '-(2-meryl-3-tert-butylamine) propoxybenzoic acid [4,-(2-hydroxy-3- (tert-butylamino) propoxy)- 3'-methoxy] -bezoic acid) yield was 45%. m melting point: 108-110. (: Proton nuclear magnetic resonance spectrum, CDCh); _____ 11 (Please read the precautions on the back before filling in this page}

Printed paper scale of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, China's CNS) A4 ^ (21 () &gt; &lt; 297 Public Fantasy • at 07141 A7 B7 Inventor B said that> 5-Adrenoceptor blockers have been widely used clinically 'and Frishman W.H. et al., 1991, Am, Heart J., Vol. 121, p. 724, report type B aggressive acceptance Device blockers are suitable for cardiovascular diseases such as hypertension, upper ventricular arrhythmia, angina pectoris, myocardial hypertrophy, myocardial infarction, etc. Overall, y5-adrenoceptor blockers are useful for type B irritants. Receptors are competitive. However, according to years of research, such as Harting J. et al., Reported in 1986, Forch / Dmg Res., Vol. 36, No. 1, p. 200, the difference between the two lies in the existence of 々! Does' selectivity 'have different pharmacological properties such as ISA' intrinsic sympathomimetic activity, cell membrane stabilization activity, fat solubility, and pharmacokinetics. The inventor of Gen. Pharmacol. 1993, Vol. 24, p. 1425 Reporting tool Cardiovascular diastolic type B receptor receptor blockers are also important for the blocking properties of calcium channels. According to Erhardt PW et al., 1982, J. Med. Chem., Vol. 25, p. 1402 Some ultra short-acting-blocker 'USABB's are safer for critically ill patients who need a type B receptor antagonist than using a long-acting antagonist. Its main advantages, For example, Quon CY et al. Reported in 1986, J. Pharm. Exp. Ther., Vol. 237, p. 912, that continuous infusion of ultra-short-acting type B agonist blocker (USABB) can quickly reach a stable concentration, and once the infusion is stopped, Immediately discontinue the effect. Because of the selective acceptance of type B 々1, this paper is compliant with China National Standards (CNS) A4 specifications (2 丨 0X297). (Please read the precautions on the back before filling this page.) ., ιτ 2 ^ 07141 A7 B7 V. Description of the invention ()

o-ch2-ch-ch2-nh-ch &lt; C

OH ch3 CH, CH2-CHrC-0-CH3 o The esmolol blocker Esmolal printed by the Shellfish Consumer Cooperative of the Central Bureau of Quasi-Ministry of Economic Affairs has the structure shown in formula (I) ' It is easily metabolized by blood and liver esters as shown in Figure (1). Therefore, Benfield P. et al., Drugs, Vol. 33, p. 392, 1987 suggested 'For periods of hyperactive hypertension (Perioperative hypertension), supraventricular rhythm Patients with acute malformations and myocardial ischemia should be administered ultra-short-acting type B blockers (USABB) for disease control. In addition, the ultra-short-acting agonistic blockers of cardiovascular diastolic effects are not only interesting, but, as reported by Reilly, CS, et al., 1985, Clin. Pharmacol. Ther., Vol. 38, p. 579, compared with administration of B alone The simple effect obtained by the type of agonistic blocker is of greater significance. Bodor et al. Reported in 1988 that metoprolol was esterified to form inactive structural metabolites. The systemic efficacy period and the activity of type B agonist were shorter than those of metoprolol and decline. Recently, Iguchi, S. et al. Reported in 1992 Chem. Pharm. Bull. Vol. 40, p. 1462 that they discovered type B irritability such as morpholino type, Esmolol type, and urea type. The blocker has the activity of an ultra-short-acting type B aggressive blocker (USABB). — .— II. ^ J— n ball (please read the note $ on the back before filling out this page) This paper size is applicable to China National Standard (CNS) M specifications (210X297 cm). Cooperative printed A7 B7 5. Description of the invention () In 1993, the inventor discovered that certain compounds with vanilloid structure have the activity of a type of adrenoceptor blockers. Later, in the research of the series, it was learned that these vanilloid type i5-blockers are a series of derivatives belonging to phenoxypΓopanol-araine. It is a spice compound with a 3-methoxy 4-hydroxyphenyl structure. Moreover, in vitro experiments in animals (/ 77) have confirmed that these vanillin ester structural compounds possess sensory and autonomic cardiovascular system activities, even if the compounds are eliminated using alkylated 4-hydroxyphenyl structures The spicy taste still retains the cardiovascular diastolic effect of the compound. In a 1992 report by lguchi, S. et al., A few type B agonists with vanilloid basic structure can be presented, Ultrashort-acting type B agonist blocker (USABB) activity. The present invention &quot; 呱 索默 an ultra-short-acting vanillyl ester type B receptor receptor antagonist with cardiovascular diastolic effect reveals a novel Vasomolol series compounds and synthetic methods. That is, products obtained through vanilloid base and vanillic acid ethyl ester. In addition, the present invention also discloses the pharmacological activity of the compound This vassomolol compound has the potential to include inhibition of the type B adrenoceptor's relative Selective, ultra-short-acting type B agonist blocker (USABB) effect, cardiovascular diastolic effect, but no endogenous sympathetic nerve activity (ISA). This paper size applies the Chinese National Standard (CNS) A4 specification (2丨 0X297 mm) ---------- Meal ------- ΐτ ------- J. (Please read the notes on the back before filling this page) 4 407141 A7 B7 V. Explanation of the invention () π. The novel vassomolol compounds of the present invention are shown in formula (II), wherein the substituent of R 1 is hydrogen or C 4 alkyl, that is, including saturated and unsaturated states. alkyl.

0-CH2-CH-CH2-NH-C ch3o,

OH COR, / CH3 CH, The novel vasomolol series compound of the present invention is printed by the Central Laboratories of the Ministry of Economic Affairs of the Central Bureau of quasi-government, as shown in formula (Π), and its synthesis method is shown in (2), It can be alkalized by vanillic acid or vanillin in advance with an appropriate alkaline solution, and the temperature can be controlled to add epichlorohydrine or epibromohydrine at room temperature. ) And then reacted with butylamine compounds under reflux to prepare. The product was crystallized, and the purified product was measured for physical analysis such as elemental analysis, mass spectrometry (MS), infrared spectroscopy (IR), hydrogen nuclear magnetic resonance spectroscopy (lH ~ NMR, CDCh), and ultraviolet absorption (UV). Can show the structure of new compounds. In order to determine the activity of a vasomolol-like compound derivative, the present invention uses an appropriate experimental mode to evaluate the pharmacological activity. Effects on heartbeat and blood pressure; 0.1, 0.5, 3.00fflg / kg of different doses of 呱 默 sommer through intravenous administration to anesthetized rats, as shown in Table (1) found that various doses can cause this paper to apply China Gujia Standard (CNS) A4 specification (2 丨 0X297 mm) (Please read the note on the back first # Save this page and fill in this page) Packing. Order &quot; 5 Central Consumer Standards Bureau, Ministry of Economic Affairs, Consumer Cooperatives, printed 407141 at _B7 V. Explanation of the invention () The effect of lowering blood pressure and heartbeat, and similar results can be obtained after the same dose of Esmolol. The administration of propranolol, a traditional type B blocker, causes a sustained increase in blood pressure in normal rats, which is obviously different from the hypotensive response shown by vassomolol and eschmer. The bradycardia duration induced by Pupner was greater than 60 minutes, while the response presented by vassomolol and Eschmer could not be maintained for 10 minutes. The continuous infusion of 300 # g / kg per minute to Esmolol and Esmolol still could not suppress the booster response induced by intravenous administration of 10 # g / kg phenylephrine. . For the effect of type B agonist, intravenous administration of 0.5 # g / kg of isoproterenol (isoproterenol) every 10 minutes for 30 minutes can speed up the heartbeat, when 100 // g / kg per minute As shown in Figure (3), the continuous infusion method was administered to Eschmer or vasomolol as shown in Figure (3). It can be found that the heartbeat acceleration phenomenon was immediately suppressed, and after 10 minutes of continuous infusion, the heartbeat inhibition phenomenon could immediately maintain a stable state. Once stopping the infusion of esniolol and 呱 somer, the type B agonistic blocking effect can be restored in half at about 8.6 soil for 1 minute and 09.5 ± 1.0 minutes (average error of ±), and there is no difference between the two. Show meaningful differences. For phenylephrine and high-concentration potassium, the Chinese paper standard (CNS &gt; A4 scale (210x297 mm)) is applicable. I nnt Inf— nn · BUI— ml I ^^^^ 1 al ^ i— 1 ^ 1 ^ 1 He — wear i (please read the precautions on the back before filling this page) 6 Printed by the Shellfish Consumer Cooperative of the Central Government Bureau of the Ministry of Economy «-407141 at B7 V. Description of the invention () For guinea pigs Atrial and trachea exhibit the activity of type B stimulators. Sommercox resists guinea pig right atrial muscle fibers (atrial strips) induced by isoproterenol (positive chronotropic actions). ). After adding 5X10-8 ~ 1 (Γ6M concentration of vasomolol), the concentration response curve of isoproterenol is shifted to the right as shown in Fig. (5-A). Osomomer can still antagonize isopropyl Epinephrine-induced electrical stimulation of guinea pig left atrial muscle fibers has a concentration-dependent contraction-enhancing effect (positive inotropic responses); and causes the cumulative concentration-response curve that shifts to the right with increasing dose of isoproterenol Figure (5-B). The activity of ySi beta receptor receptor possessed by vasoraolol is shown in pA2 値 shown in Table (2), showing that the activity of 呱 Simer is stronger than that of Atina (Atenolol), slightly stronger than metoprolol, but weaker than propranolol. The guinea pig tracheal fibers are induced by serpin in the autonomic tension of 0.5 # g / kg isopropyl The diastolic phenomenon exhibited by isoproterenol can be completely cleaned by vasomolol at a concentration of 5X10 8 ~ Ιί 6 Μ; as shown in Figure (5-C), its concentration response curve is shifted to the right to the curve of the antagonist The concentration response curve of the antagonist of the left atrial myofibers is also corrected according to the same situation. As shown in Table (2), Ph 値 ', 呱 呱 默 Sommer has a type 2 irritant receptor blocker activity that is better than that of pupenaide. Weak ^ This paper size applies to China National Standards (CNS) A4 (210X297 cm) (please read the note on the back before filling in this page) r 7 407141 A7 B7 V. Description of the invention () Fox Sommer ( vasomolol); the selectivity of $ 1 and 10,000-^-^ 1 ^^^ 1 m nn ^ 1 · nn ^ i an ^^ 1 1 ^ 1 ^ SJ (Please read the notes on the back before filling this page) According to the method described by Baird JRC and others in 1972, J. Pharm · Pharmacol. Vol. 24, p. 880, the right atrium and the trachea are different. Taking pA2 logarithmically, it was found that Vasomolol's right atrium was 39.8 times larger than that of the trachea, which had a selectivity of yS i. As shown in Table (2), pa2 値 in propranolol's right atrium is 1.3 times that of the trachea, so it is not selective. · Vasooolol lacks endogenous sympathetic nerve activity (ISA). The frequency of right atrial contraction and left atrial tension induced by serpin are increased through the increase of solsol, esmolol, Propyl adrenaline (isoproterenol) 'propranolol is measured in a cumulative manner, as shown in Figure (6). Increasing the cumulative concentration of isoproterenol printed by the Consumers ’Cooperative of the Central Prospectus Bureau of the Ministry of Economics may increase heartbeat When it is added at a concentration of W6M, the heartbeat frequency reaches the highest. Vasomolol can neither increase heartbeat nor promote contraction. When it is added at a concentration higher than 1 (Γ5μ, the heartbeat decreases and the contraction tension decreases. Propranolol also causes a decrease in heartbeat as its concentration suddenly increases. A similar inhibition phenomenon of contraction tension reduction; when its concentration is 10-4 ~ 1 (Γ3 Μ, Pupner is sufficient to cause the heart to stop or unable to excite. This paper size is applicable to the Chinese National Standards (CNS &gt; Α4 said grid ( 210 × silicon 7 mm) 407141 A7 _____B7_ 5. Description of the invention () The effect of vasomolol on the binding of radioactive substances is shown in Figure (7). [3H] -DHA is combined with the guinea pig ventricular membrane. The concentration varies with the standardized compound, usually G.1 ~ 30 ιM. According to the analytical method described by Scatchard, G. in Acad. Sci. 1949, Vol. 51, p. 660, the degree of binding (affinity) and binding can be determined. Quantity. The equilibrium separation constant (Kd) 値 is 8.1 ± 0.9nM (average error), and the maximum binding capacity (Bmax) is 120.3 per milligram of protein at 25 ° C. ± 6.0 framol / mg (average mean error). Combined with [3H] -DHA, the reaction is close to equilibrium in about 20 minutes, and the equilibrium state is maintained for 90 minutes. As shown in Figure U), the type B stimulator Antagonist in the ventricular membrane combined with the print of ml of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs.---II HI HI 1 ^ 1 HI. In ^^ 1 ^^ 1 ^^ 1 (Please read the precautions on the back before filling (This page) 〔3H〕 -DHA shows the competition curve of the binding position. The 1C50 of non-selective propranolol is 33.1 to 4.5 nM, while vasomolol and esmolol are 4.7. ± 1.5 and 5.0 ± 1.3 (private M). Therefore, the inhibition of [3H] -DM binding intensity of beta receptor receptors is in the order of Puppennay> 呱 Sommer = Eichmer. The 呱 Sommer of the present invention ( Vasomolol) series of compounds can be made into lozenges or other solid preparations by adding various excipients, such as magnesium stearate, corn flour, starch, lactose, sodium methyl cellulose, ethanol, glycerol, etc. Buffer-like solution to adjust pH pH 碱 can be made into injections or other liquids and various dosage forms. An injection 25~100 mg, China National present paper rubbing scale applicable registration (CNS) A4 size (210X297 male |) A7 B7 407141 V. invention is described in () the solid preparation 3~500 mg two to three times per day. Illustration I. I n--I----.---- III (Please read the precautions on the back before filling this page) Table (1) Blood pressure and heartbeat data sheet (2) #! 乙 激Sex receptor blocker activity diagram (1) Esmolol metabolism state diagram (2) fox somol (vasomolol) series of compounds synthesis method. Figure (3) for the role of type B blocking agent a. Esraolol b. Vasomolol c. Stop infusion map (4) Inhibition of rat aortic contractile response (A) Response induced by high concentration of potassium (K +) (B) Demethylation Response diagram induced by phenylephrine (5) For the activity of guinea pig atria and trachea showing B-type stimulatory receptors Consumer cooperation by the Central Standards Bureau of the Ministry of Economic Affairs Du printed (A) Right atrium (B) Left atrium (C ) Tracheal diagram (6) Endogenous sympathetic nerve activity (A) Contraction frequency inhibition (B) Tension inhibition This paper size applies Chinese National Standard (CNS) M specifications (210X297 mm> 10 407141 A7 B7, V. Description of the invention ( ) 1. Isoproterenol (is〇Proteren〇l) 2. Propranolol 3. Vasomolol 4 Esmolol (7) Effect of radioactive substance binding (8) Competitive curve of ventricular membrane binding position 1. Propranolol 2. Wsoraolol 3. Esmolol ) Figure (9) Example of synthesis method of vassomolol compound 1 Slowly add vanadium vanillin (van i 11 i η) with 15 · 2 g I ϋ. Dissolved and in a dirty state, add equal molar sodium hydroxide and wrap the outside of the reaction bottle with ice to control the temperature below 25 ° C, and then slowly add 5 times the molar amount of epichloric acid (epi-. 111〇1: 〇1 ^ (11 ^ 116), 3 times the molar amount of tert-butylamine (161: 1; -1) 11171 &amp; 11 ^ 116), after refluxing at 55 ° C for 2 hours, the reaction was taken out The solution was concentrated under reduced pressure and crystallized from dichloromethane to obtain 3 · -methoxy-4 '-(2-acyl-3-tert-butylamine) propoxybenzoic acid [4,-(2-hydroxy -3 -(tert-butylamino) propoxy) -3'-methoxy] -bezoic acid) yielded 45%. m melting point: 108-110. (: Proton nuclear magnetic resonance spectrum, CDCh); _____ 11 (Please read the precautions on the back before filling in this page}

Printed Paper Size Quick Use of Chinese CNS by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A4 ^ (21 () &gt; &lt; 297 Ghost Magic 407141 A7 B7 V. Issue Date I Date 4 (ks,) 9H, CH3 X 3), 2.40 (br s, 1H, replaceable OH), 2.90- 3.27 (m, 2H, CH2NHC) »3.88 (s, 3H, OCH3), 4.06-4.19 (m, 3H, ArOCfl2Cfl (OH)) 5.78 (s, lH, NH), 6.90- 7.67 (ra, 3H, Ar) &gt; 12.54 (br s, 1H, COOH) &gt; Infrared spectrum (._IR, KBr) 3250 * 1700 (cra'1); Mass spectrum ( MS) m / z: 298 〔M + H〕 + CH, (Please read the note on the back before filling this page) Order printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

0-CHr CH-CH2-NH-C <CH3 'OH CH3 Example 2 To 10.2 g (33.7 mmol) 3'-methoxy-4'-hydroxypropylamidobutylamine benzoic acid [4'-(2 -hydroxy-3- (tert-buty) aniino) Chinese national standard (cns) A4 size (2 丨 ox297 mm) of this paper scale Quickly 407141 A7 B7 -iethoxy] -bezoic acid) dissolved in 5 times the amount of anhydrous Alcohol, add isomorphous thionyl chloride (SOCh) and reflux for 5 hours. Take out the reaction solution and concentrate under reduced pressure. Crystallize with a solvent mixture of propanol and ether to obtain 3'-methoxy-4,-(2-meryl group. The yield of 3-tert-butylamine) propanylbenzoate [4 |-(2-hydroxy-3- (tert-butylamino) propoxy) -3'-methoxyj-ethylbezoate) was 40%. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, melting point: 160-162 ° C hydrogen nuclear magnetic resonance spectrum dH-NMR, CDC13); 5 1.19 (s, 9H, CH3 X 3), 1.27-1.34 (t, 3H, COOCH2CH3 ) »2.42 (bs, 1H, replaceable OH), 2.72-2.96 (m, 2H, CH2NHC) &gt; 3.82 (s, 3H, OCHs) &gt; 4.06-4.20 (m, 3H, ArOCH2CH (OH)) 4.23- 4.34 (q, 2H, C00C | 2), 5.78 (s, 1H, NH), 6.90-7.67 (ro, 3H, Ar), 12.54 (br s, 1H, C00H)-infrared spectrum (IR, KBr) 3350 ' 1730, 1 600 (.〇1- 丨); mass spectrometry (MS) ra / z ·· 326 [Η + Η] + (Please read the precautions on the back before filling this page) The paper size of the book is applicable to China's national standards (CNS) A4 specification (210X297 mm) 13 407141 a7 B7 V. Example l Vasomolol 50 mg lactose 30 mg starch 4 mg magnesium stearate 6 mg corn flour 10 mg Liniment dosage form of vassomolol. -ii ^ i · n ^ ll ^ m —iBI—fl »^ — ^ 1 4 ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 —J -¾.-^ (Please read the precautions on the back before filling out this page) Printed by the Central Consumer Standards Bureau, Ministry of Economic Affairs, Employee Consumer Cooperatives This paper is printed in accordance with China National Standards (CNS) A4 (210X297 mm) 14 407141

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CD OO ^ CO CD o O ri ---------- Installation ------: — Order (Please read the precautions on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Meng Meng · wMwr This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 407141 A7 B7 V. Description of the invention () Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs β / β2 39.8 1.3 (Continent pole潞 Benben Λ ♦ Ice 渖 Eight-bed 踔 * S decision ball) ___ Do ______________ cs CO, PA2 value trachea (slope) 5.81 ± 0.11 (0 · 81 ± 0 · 06) 8.28 ± 0.09 (0.85 ± 0.08) value Left atrium (slope) 7.44 ± 0.03 (0.89 ± 0.02) 8.46 ± 0.07 (0.87 ± 0.07) CNJ 1 1 1 Order 1 CQ. PA2 Right atrium (slope) 7.4110.05 (0.90 ± 0.04) 8.40 ± 0.06 (0.92 ± 0.05) ) 1 1 1 1 s A 1 1 | β_Blocking Thanks: 呱 Someup Pannai 1 1 1 1 1 1 16 1 1 1 1 1 1 This paper size applies to China National Standard (CNS) A4 specification (210X297) %)

Claims (1)

407141 A8 B8 C8 D8 Patent Application Scope 1. An ultra-short-acting vanillyl ester-type plastic stimulating receptor with cardiovascular diastolic effect antagonizes Qi I a first pharmaceutical composition, which includes compounds such as vassomolol and its salts as the back Note for ιδ Please fill in the CH, 0 component and necessary excipients on this page; where the substituent of R1 is hydrogen or C1-4 alkyl CH, CH, NH CH, COOR Order printed by the Ministry of Economic Affairs, China ’s husband and wife consumer co-operative cooperatives | cm 7 7 2 407141 A8 B8 C8 D8 1. An ultra-short-acting vanillyl ester-type plastic stimulating receptor with cardiovascular diastolic effect antagonizes Qi I a first pharmaceutical composition, which includes compounds such as vassomolol and its salts as the back Note for ιδ Please fill in the CH, 0 component and necessary excipients on this page; where the substituent of R1 is hydrogen or C1-4 alkyl CH, CH, Ordered by NH CH, COOR Printed by the Chinese Ministry of Economic Affairs and the Standards for Employees' Cooperatives | cm 7 7 2