JPH05503510A - Compositions and methods containing optically pure (S)-atenolol - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Compositions and Methods Containing Optically Pure (S)-Atenolol Atenolol Beta -A drug belonging to the general class of compounds known as blockers. Beta blocker include beta-selective (cardio-selective) adreseptor blockers; These are exemplified by known commercially available products such as Tenormin.

Atenolol is an effective cardiac regulator, which has beta-blocking activity and antihypertensive activity. It has both barotropic activity. Atenolol's beta-adler sebuter blocking activity Gender is associated with low, resting and active zero frequency and cardiac blood output. Decrease in systolic and diastolic blood pressure during movement, isoproterenol-induced suppression of tachycardia It is characterized by a decrease in reflex tachycardia as well as reflex upright tachycardia. atenoro The significant beta-blocking effect of the drug is evident within 1 hour after oral administration of a single dose. Become. by blocking the positive chronotropic and inotropic effects of catecholamines. By lowering blood pressure and lowering blood pressure, atenolol generally reduces Reduces the heart's oxygen requirements.

Atenolol is a racemic mixture. That is, they are optical isomers, so to speak. It is a mixture of all enantiomers. Enantiomers are one type of isomer. An organic compound that differs only in that it is a mirror image of another, and mirror images are I can't sleep. This phenomenon is known as polarization. most biological Molecules exist as enantiomers and exhibit polarization. structurally identical However, enantiomers can have very different effects in biological systems. and one enantiomer is often biologically active while the other is rarely Has little or no biological activity.

Summary of the invention The present invention provides patients with a beta-blocking amount, ie, an antihypertensive amount, of substantially R(+) Administering the 5(-) enantiomer of atenolol without enantiomers A method of treating patients with cardiovascular diseases such as angina and hypertension, consisting of: It is related to. The method is useful in the treatment of cardiovascular diseases and in the treatment of hypertension. While being useful, it reduces (reduces or eliminates) undesirable side effects. child In these applications, beta-blocking and antihypertensive drugs reduce these side effects. It is important to obtain a blood pressure composition. The 5(-) isomer possesses these desirable properties. Since the composition containing the 5(-) isomer of atenolol exhibits both Particularly useful in applications such as

The method is useful for the treatment of heart diseases associated with eg angina pectoris and/or hypertension. Useful.

Brief description of the drawing Figure 1 shows isoprenaline (0.05 μg/kg , intravenous) on induced tachycardia (6 beats, HR) and diastolic blood pressure (DBP) responses. Figure 2 is a graph showing the effect of various amounts of R5, R or S atenolol.

Figure 2 shows the effects of various amounts of R5 on resting 6-beat frequency in rats that underwent spinal taping of the brain. , R or S atenolol.

Figure 3 shows various contraction tensions of isolated electrically evoked arterial muscle preparations. The present invention shows the effect of R3, R or S atenolol in amounts of To enhance beta-blocking activity after or associated with hypertension as well as beta-blocking 5(-) atenolol to reduce undesirable side effects associated with drugs. Regarding the beta-blocking activity of the 5(-) levorotatory enantiomer of atenolol It is something.

The letters R and S indicate the configuration of the chemical substituents forming the enantiomeric center. Refers to position or relative position. For atenolol, the S configuration is levorotatory. That is, it is the (-) enantiomer, and therefore the R configuration is dextrorotatory, that is, the (deca) enantiomer. It is an thiomer.

In this method, 5(-)-ate is substantially free of its R(+) enantiomer. Norol alone or in combination with other drugs in adjunctive therapy e.g. patients suffering from cardiovascular diseases such as angina, angina, or hypertension. child "rS(-)atenolol" used herein means 4-[2'-hydroxy- 3'-[(1-methylethyl)aminocopropoxybenzeneacetamide S left It is a rotatory isomer. As used herein, "substantially the R(+) enantiomer The term "does not contain" means that the composition contains only a small amount (at least 90% by weight of 5(-) atenolol). and 10% by weight or less of R(+) atenolol.

S(-)atenolol can be obtained by purification from racemic atenolol or by unpaired Obtained by symmetrical synthesis technology.

Racemic atenolol contains a mixture of R(+) and 5(-) enantiomers. have. The 5(-) enantiomer is the most active of these enantiomers. The larger beta-blocking agent is the pharmaceutically more effective form of atenolol. be. That is, to produce a certain effect, a smaller amount of S than in a racemic mixture is required. Requires the (-) enantiomer. 5(-) enantiomer is a racemic mixture S enantiomers are about twice as effective and therefore about half the dose of the racemic mixture. Omer has comparable beta-shielding activity.

Some of the undesirable side effects associated with administration of atenolol may be due to its shielding activity. Therefore, the more effective beta-shielding stereoisomer, i.e., the S(−) enantiomer The reduced dose made possible by the use of Omer would reduce the chance of adverse effects. cormorant.

In this method, 5(-)atenolol is used to treat cardiac problems such as angina pectoris or hypertension. Administered to patients suffering from vascular disease. For example, 5(-) atenolol is therapeutic It is administered to patients after a heart attack, or to reduce hypertension and regulate heart rate. Administered to correct the condition. On the other hand, 5(-) atenolol may cause a heart attack. It can also be administered prophylactically to reduce

Unless otherwise specified, all amounts and percentages are by weight.

The drug may be administered orally, by subcutaneous or other injection, intravenously, topically, parenterally. e.g. can be administered by an implanted reservoir containing the drug. Administration of drugs The form (e.g. powder, tablet, capsule, solution, emulsion) depends on its mode of administration. Will. The dosage of drugs is determined on an individual basis, and at least in part Based on the size of the patient, the severity of the condition being treated, and the desired outcome. Dew. In general, a sufficient amount of 5 to reduce high blood pressure and regulate mood (−) Atenolol will be administered. For example, about 100 mg or less per day. (and e.g. 40 mg or less per day) 5(-) atenolol one or more times is administered to produce the desired effect. However, some patients with angina may require up to about 200 mg per day, and in such patients 1 80 mg per day can be given. Typically about 20 to about 5 per day 0 mg (e.g. 20-20-4O of 5(-) atenolol will be administered) cormorant.

The methods of the invention include administering S(-)atenolol in combination with one or more other drugs. can be done. For example, thiazide-type diuretics, calcium channel blockers, hydrara Other antihypertensive agents such as gin, prazosin, and alpha-methyldopa (-) Can be given with or about the same time as administration of atenolol. 2 types ( Atenolol, which is a drug (above), and other drugs in one composition or two It can be administered as a separate object. For example, combine them into one capsule, It can be administered as tablets, powders, liquids, etc. or as individual compounds.

5(-)Atenolol and other drugs or drugs contained in the specified composition. The ingredients to be used are predetermined by the method of administration of the composition. For example, in tablet form, Compositions to be administered orally may contain, in addition to drugs, fillers (e.g. lactose), Binders (e.g. carboxymethyl cellulose, gum arabic, gelatin), adjuvants , fragrances, colorants and coating substances (e.g. waxes or plasticizers). can have Compositions intended to be administered in liquid form may contain combinations of drugs. It can also optionally contain emulsifiers, fragrances and/or colorants.

Generally, according to the method of the invention, 5(-)atenolol alone or in combination with It is attempted to treat patients by administering them periodically as needed in combination with drug(s). The desirable benefits associated with beta-screening agents while reducing symptoms of hypertension or angina No side effects are reduced or eliminated.

The length and dosage of the drug will depend on the disease being treated, the type of condition and It will depend on the weight as well as the physical condition of the patient being treated.

The invention is illustrated by the following examples. These examples are not intended to limit the invention. It's not something you do.

Production of aom-nitrobenzenesulfonyl chloride 112.5g (0.5mol The m-nitrobenzenesulfonic acid sodium salt of Placed in a round-necked flask. Thionyl chloride (119 g, 1 mol, 73 mL) was added to the solid. ) was added. While stirring the concentrated material slowly, add 25 mL of DMF in approximately 1 minute. I added it across. The material began to heat up and liquefy (T about 40°C). Stir for 1 hour After pouring the clear solution into ice/water, an oil was obtained which solidified rapidly. solid was thoroughly washed with water, dissolved in methylene chloride, and dissolved on anhydrous magnesium sulfate. It was dried. Crude m-nitrobenzene by stripping methylene chloride The sulfonyl chloride was obtained as an oil, which solidified rapidly.

Yield = 110.8g (100%).

This material was recrystallized from EtOAc/hexanes (approximately 50150) at 72. Yielded 8g of pure material (66%).

b. Production of glycidyl m-nitrobenzenesulfonate (R)-glycidol ( 148 g, 2.0 mol) and EjsN (304 ml, 2.2 mol). The solution of toluene in toluene was cooled with ice water (approximately 5°C). Keep the temperature below 10℃ Then, m-2 upper benzenesulfonyl chloride (426 g, 1.92 mol) was added. Added portion by portion. A white precipitate (Et3N-HC1) formed during the addition.

The mixture was stirred at room temperature for 22 hours. Then dilute the mixture with a small amount of EtOAc and and filtered.

The solid residue was thoroughly washed with EtOAc. The filtrate was then concentrated to dryness to give a yellow solid. , when it was left to stand and cooled, it became a solid. Optical rotation does not change (Naruma) The solid was recrystallized twice from EtOAc/hexane.

1st collection l: Weight: 321g [Alpha]” = +22.5 (c = 2.16, C HCl3) Second recovery amount: Weight: 72g [Alpha]” = +23 (c = 2.16, CHC l,) 393g 79% yield ! it[alpha]”=+23 (c=2.14, CHCl,) Third recovery amount: Weight: 36g [Alpha]” = 417.5 (c = 2.14, C HCIm) Production of c,5(-)atenolol In a 2 liter three neck round bottom flask equipped with a top stirrer, 240 g of p-hydrocarbon Xyphenylacetamide was dissolved in 600 mL of dry DMF. ice the solution Cooled to about 15°C with water. Keep the temperature below 15℃ (actually 10℃-15℃) While adding KOMe (117 g) in portions via a solid-powder addition funnel, Ta. After the addition, the ice water was removed and the resulting white suspension was incubated at ambient temperature for 1 hour. Stir for a while. Next, while keeping the temperature below 20'C with ice water, add 400 mL of DMF. Glycidyl m-nitrobenzene sulfonate was added. During the addition, the mixture It became very thick and difficult to stir, and local exotherms were observed. Therefore, The mixture was transferred to a 4 liter reactor using 1.5 liters of DMF. what happens next The resulting suspension was stirred for 23 hours (TLC: complete reaction).

The mixture was then filtered and the remaining solids were thoroughly washed with a small amount of DMF.

The combined filtrates were then concentrated to a volume of approximately 1 liter.

Transfer the concentrate to a 2 liter three neck round bottom flask equipped with a reflux condenser and magnetic stirring bar. I added it inside. Add 510 mL of 1-PrNH2 and 10 mL of H2O to the flask. added to. The resulting solution (orange color) is stirred until all the glycidyl epoxide is consumed. Refluxed for 5 hours.

The solution was then cooled and concentrated under vacuum to remove DMF. Yellow solid obtained was then stirred with 2 liters of 3% NaOH solution until a fine suspension formed. Ta. Filter the mixture and fill the resulting solid with a small portion of water until the filtrate is colorless. Washed for minutes.

The resulting 5(-)atenolol solid was then purified from 1-PrOH and water (16:d). Recrystallized.

Example 2 Comparison of the pharmaceutical effects of S(-), R(+) and racemic atenolol a, for experimental use Formulation and process (i) Isolated tissue preparation Studies were performed on isolated chambers and tracheal axes of rats and guinea pigs. All of Equilibrate the tissue with Krebs-Henseleit physiological salt solution for 6° [minutes]. where the composition of the solution is NaC+, 118; KCI; 4.7:Mg5O,,1,2;CaCl2.2.5:KH,PO,,1,2; NaHCo, 25　; 7" Russ: +-su, 11,1, UEDTA, 0.00 257-There was.

. Van Rossuw (＾rchiv, rnt, Pharmacodyn, 1 (Dan, 299-329.1963) Cumulative concentration-response curves were obtained in each formulation as described in - (Zaborowsky) et al. (J, Phar+aacol, 1leth, , Sho, 165-178.1980). I let it happen. To measure antagonistic properties, at least one concentration of the first control concentration-response curve is After 45 minutes, add appropriate reagents to the organ bath and allow to equilibrate for 20 minutes. , and then created the following concentration-response curve. The shift to the right side of this curve is the pA2 value (Mackay, J, PharrA, Phar+5aco1. 30.312-313.1978).

(ii) The preparation of a mouse whose brain was subjected to spinal tap was applied to a mouse weighing approximately 200-250 g. Anesthetize with rotane, insert a cannula into the left carotid artery and left jugular vein, and insufflate the left carotid artery and left jugular vein. The tube was exposed and a cannula was inserted. Let the animal breathe artificially and Later, spinal puncture was performed on the brain. While measuring blood pressure and 60°C from the left carotid artery, Drugs in normal saline were administered via the left jugular vein. Under these conditions, the brain is The formulation in rats subjected to pricking was stable for at least 4 hours.

(a) Antagonist property To measure beta-adrenocebuter antagonist activity, 0.05 μg/kg of i.v. Soprenaline was initially given three times at 10 minute intervals, and the control response to 6 beats was determined. Created. When these effects are reproducible, the first trial of the test drug (antagonist) administration, followed 5 minutes later by a standard dose of isoprenaline. gradually higher The regimen was repeated at 15 minute intervals using a dose of antagonist. Dosage range is logarithmic Series 0.1.0.3.1.0.3.0.10.30.100.300.10 00.3000 and 10. Teita based on OOOug/kg.

(b) Worker muscle activity To measure agonist muscle activity, a dose range of 0.1-10,000 ug/kg IV Increasing the dose of test drug or isoprenaline to test for cumulative drug effects The effects on hepatic frequency (beta) and blood pressure (beta2) were studied.

b. Pharmaceutical effect (i) Activity against beta-1 and beta-2 adrenocebuter (a) Isolation prepared formulation Stereoisomers as competitive antagonists at different beta-adler receptor sites Relative abilities can be expressed as I)A2 values (Tables 1 and 2).

The method used to measure pAx values was adapted from the description of Matsukei. Frequently To measure pA2 for pulse depression, we first measured only the response to isoprenaline. and then recorded the response to isoprenaline in the presence of antagonist. . The concentration of inbrenaline that produced 50% inhibition of the maximal response (IC50) was determined in the presence of antagonist. measured in the presence and absence of Defined as the difference. Next, 1) A2 is calculated using Matsukei's formula for dose ratio and antagonist. Measured using molar concentration.

In vitro pharmaceutical studies are performed on isolated chambers of both rats and guinea pigs. It was.

The results obtained in the rat chamber are shown in Table 1. In these studies, R and S Isomers were supplied by Supracoll, Inc.

The racemic mixture is available from Sigma as a standard commercial formulation or as an equivalent amount of Cebraco. obtained from a combination of le isomers. In the mouse room, beta 1-adrenose In the butar formulation, S- The pAx value of atenolol was about 7.6. This indicates that the relative S-isomer This indicates that the physical capacity is 18-52 times that of R. Sigma or Cebracol? The pA2 of racemic atenolol obtained from 10. from R-isomer only. =20 times larger but 1.8-2.5 times smaller than the S-isomer shows great ability.

The results obtained in the guinea pig chamber were similar.

Two beta-2 adrenocebuter formulations were used. They are isolated mice uterus and isolated guinea pig trachea, again with isoprenes as the working muscle. Narin was used (Table 2). In the mouse uterus, 4,7 for R-atenolol. The pAz value of S-atenolol is about 6, and the pAz value of S-atenolol is about 6, and (manufactured by Sigma) was 5.8.

Thus, S and racemic forms are 19 and 11 times more effective than R atenolol, respectively. Met. Results obtained with a second beta-2 preparation in the trachea of guinea pigs also Similarly, it is 11 times more effective than the R isomer, and the racemic mixture is 8 times more effective than the R isomer. It was twice as effective.

Table 1 Atenolol isomers relative to beta-1 adrenocebuter in vitro ability pA2 (average ±SEM) R (+) atenolol 5 (-) atenolol (shi atenolol) (rat) (i) Sepracol (su(-): sigma(±)1) A2 5.91±0.17 7 ．． 63±0.07 7.23±0.15n 8 10 11 Relative ability 1 52 21 (ii) Sepracol (+X-): (±) pA26.51±0.24 7.67± 0.21 7.5 Kano 0.16n 6 11 11 Relative ability 1 18 9.8 (b) Guinea pig Sepracol (+X-): Sigma (±) p A2 5.8±0.13 7.43±0.13 7.24±0.12n 8 14 7 Relative ability 1 43 28 Table 2 Atenolol isomers relative to beta-2 adrenocebuter in vitro ability Isolated rat uterus (B2) or isolated mouse uterus using isoprenaline as the agonist pA2 in the trachea of guinea pigs (mean ± SEM) R(+) atenolol 5 (-) Atenolol (± atenolol) (a) Rat uterus (1) Sepraflu (+) (-); Sigma (±)pA 2 4.74±0.44 6.05±0.11 5.80±0.25n 6 8 6 Relative ability 1 19 11 (b) Guinea pig trachea Cebracol (+X-); Sigma (±) pA　2　4.42±1.0　5.4g±1.0　5.3±0.12 Relative ability 1118 (b) Preparation in rats whose brains were subjected to spinal taps. A rat was used. Prepare the anesthetized animal for blood pressure and pulse recording. Next, spinal puncture was performed on the brain. Adrenocebuter antagonist activity using this formulation The gender was evaluated. A standard dose of isoprenaline of 0.005 μg/kg was administered to induce tar-mediated tachycardia and evaluate inhibition of this response by continuously administered antagonists. I valued it. The antagonist ID5o is the concentration that suppresses the isoprenaline tachycardia response by 50%. be.

Isoprenaline also produces beta-2 adrenocebuter-mediated reductions in blood pressure. Ru.

As shown in Figure 1 and Table 3, both S and racemic atenolol are Although the agonist effect of isoprenaline on 6°C was suppressed in a dose-dependent manner, blood pressure The effect of isoprenaline on , which means that they both have considerable beta selectivity in this model. It shows that it was done.

ID. From this, the S isomer is 6 times more effective than the racemate and 90 times more effective than the R isomer. there were. The S isomer is the most effective at inhibiting the ability of Inbrenarin to reduce blood pressure. is also valid, but its relative power to other forms is ID,. In this formulation, exactly Obviously, it could not be established because it could not be measured.

Table 3 Average ID50 of atenolol in rats whose brains were subjected to medullary puncture (β): 99.5 ±21μg/kg 1480.8±554.1ag/kg 16.5±1.11 IDs of atenolol in mice (β2) with og/kg brains subjected to medullary puncture.

(Racemic body) ± (R) + (S) − >10.000 >to, 000 3000 >10.000 >10.000 5370>10.000>to, ooo' 4786>10.000> 10.000>10.000>10.000 Average >10.000μg/kg >10. OOOag/kg 5798±17 22 μg/kg IDso ratio - ability for β1/β2 (Racemic body) ± (R) + (S) − 100, 506, 75350, 85 (i) Intrinsic sympathomimetic activity (rsA) in the stereoisomers of atenolol To assess the presence of agonist agonist activity (ISA), we also used mice that underwent brain puncture. did. This was dose dependent at 0°C, which was masked by propranolol. as an increase in sex (beta 1) or a dose-dependent decrease in blood pressure (beta 2). It should be obvious. Beta 1 with any form of atenolol studied Or there was no sign of Beta 2. In contrast, all three forms of Atheno The role is similar to the dose-dependent suppression of resting frequency independent of constant blood pressure changes. The level is shown (Figure 2).

(iii) Cardiac depressant effect Negative inotropic effects of stereoisomers studied in detail in electrically induced arterial preparations did. By comparing concentrations in the presence of atenolol to control contractions. We estimated a negative inotropic effect. Data expressed as % change in pull has been done. Propranolol (R/S) is used in this formulation and it produced a clear dose-dependent effect at high concentrations.

The various isomers of atenolol have reduced contractile force to a lesser extent than propranolol. It was also effective when Unable to distinguish between different forms of atenolol (Figure 3).

Atenolol (, qg/kg, 1.V,) International Search Report Ql”T/IIc Q. /nlOMPCT/US901061i24 international search report ,XS%gg367824 0 shots Author Lewis, William Jay Massachusetts, United States 01742 Concord Blue Bay IJ- (no address)

Claims (9)

[Claims] 1. For the production of drugs for the treatment of cardiovascular diseases and at the same time associated with beta blockers. Substantially R(+) atenol to reduce or eliminate undesirable side effects Use of S(-) atenolol without alcohol. 2. Use according to claim 1, wherein the cardiovascular disease is hypertension or angina pectoris. 3. Claim 1, wherein the amount of S(-) atenolol in the drug is greater than about 90% by weight. Use as described. 4. Claim 1, wherein the amount of S(-) atenolol in the drug is greater than about 99% by weight. Use as described. 5. The amount of S(-)atenolol in the drug may reduce or improve symptoms of cardiovascular disease. 2. The use according to claim 1, wherein the use is sufficient to remove 6. up to about 100 mg S(-)atenolol and preferably about 50 mg S(-) -) for producing a unit dosage form of a medicament comprising atenolol, as claimed in claim 1. Use of. 7. For the production of drugs for the treatment of cardiovascular diseases and at the same time associated with beta blockers. S(-) atenolol and and the use of at least one other drug. 8. Other drugs include antihypertensives, such as thiazide-diuretics, calcium channel blockers, 8. Doralazine, prazosin or alphamethyldopa. Use of listed. 9. Substantially R(+) atenol for the manufacture of medicaments for the treatment of cardiovascular diseases. Use of S(-) atenolol without alcohol.