TWI257306B - Pharmaceutical composition for treating heart rhythm disturbances comprising N6-substituted-5'-(N-substituted) carboxamidoadenosines - Google Patents

Abstract

The present invention discloses a method for treating heart rhythm disturbances in a mammal in need thereof by the administration of N6-substituted-5'-(N-substituted)carboxamidoadenosines. More particularly, the invention is directed to a method for treatment of heart rhythm disturbances in a mammal that would benefit from the induction of negative dromotropic and/or negative chronotropic actions, comprising the administration to said mammal an effective amount of a compound of the formula, or a pharmaceutically acceptable salt or ester thereof; wherein R1 is C3-7 secondary alkyl, or C3-8 cycloalkyl; and R2 is C1-4 alkyl or C3-5 cycloalkyl The invention is also directed to novel dosage forms comprising said compounds.

Description

1257306 A7 B7 V. INSTRUCTIONS (2) For the treatment of p S V T, but the effect of converting A F to normal sinus rhythm is not confirmed. (Please read the precautions on the back and fill out this page.) Adenosine is a multi-receptor subclass called A i, A 2 A, A 2 B and A 3 . The negative shift and negative transduction of the adenosine A i receptor adenosine directly inhibits the contraction of the atria (but not the ventricle). Coronary artery dilatation of adenosine A 2 a receptor adenosine. The location and function of adenosine A 2 B and A 3 receptors in the heart are not clear. Because P SVT can be derived from abnormal tachycardia affecting the AV node and negative transduction of adenosine A i receptor adenosine, the strategy of terminating PSVT is to slow the menstruation with a selective adenosine A i receptor agonist. Pulse of AV knot (Beardinelli et al., Journal of Pharmacology and Experimental Therapeutics 271:1371 (1994); Snowdy et al., British Journal of Pharmacology 126: 137 (1999)) o However, this gland has been studied for this purpose. The glycoside A i receptor agonist lacks the required strength, selectivity, oral bioavailability, and/or pharmacodynamic activity. Further, adenosine A in the prior art has been shown to cause hypotension, which is a side effect of worsening symptoms for arrhythmia. The Ministry of Economic Affairs' wisdom and wealth 43⁄4 employee consumption cooperatives have previously reported a series of N 6 - substituted 5 '- (N-substituted) carboxyguanamine adenine nucleoside derivatives. These compounds are selective glandular ridge A 1 receptor agonists (〇1 ss ο η, R · and T h 〇mps ο η, R., U. S Patent Ν〇 5, 310, 731 ) for use as vasodilators or antihypertensives. Agent. SUMMARY OF THE INVENTION The present invention is directed to mammals benefiting from negative transduction, negative shifting # -5- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1257306 A7 B7 V. Description of invention ( 3) The action, or a combination thereof, induces a treatment for arrhythmia' includes: administering an effective amount of a compound of formula 1 to a mammal in need of such treatment

HN I Ministry of Economic Affairs Intellectual Property Employee: ^ 费 汴 汴 印 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Department C 1-4 yard base, C 1-4 through the hospital base or C 3-5 ring yard base. These arrhythmia include supraventricular tachycardia, such as paroxysmal supraventricular tachycardia (PSVT) and atrial fibrillation/jitter (AF). The invention also contemplates novel intravenous or oral dosage forms comprising one or more compounds of formula I at a particular concentration. The invention also contemplates the use of a compound of formula I for the benefit of a mammalian benefit from a negatively variable, negatively variable action, or a combination thereof, which induces the treatment of arrhythmia. Brief description of the figure Figure 1 N 6 - cyclopentyl gland - 5 ' - aldose amine (Compound A) in the scorpio isolated from the heart of the negative and negative shifting effect; HR = heartbeat, Bpm = beats per minute, msec = milliseconds. Compound A produces a V conduction slowdown depending on the concentration, and the highest a V interval increases. - (Please read the back note first and then fill out this page) 4 This paper size applies to the Chinese National Standard (CNS) A4 specification (210X) 297 mm) 6 1257306 A7 B7____ V. Description of invention (4) Add 3.4% above the base. Compound A also produced a decrease in heart rate due to concentration, E C 5 .値3 · 2 η Μ and the heart rate is reduced by up to 58%. (Please read the precautions on the back and then fill out this page.) Figure 2 Compound a in the guinea pig's paroxysmal supraventricular tachycardia (p SVT) isolated negative model of the heart model; HR = heartbeat, bmp = Heart beats per minute, msec = milliseconds. The compound A' has a small effect on the A V interval of the 2 0 0 b p rhythm at an average concentration of 2 n , , and induces the A V partition within 30 seconds during the 3 0 b b m rhythm. When the rhythm returns to 2 〇 〇 b m p, the A V interval returns to near normal 値. The effect of Compound A in this experimental model of P S V T is thus dependent on rate and Compound A produces a greater increase in A V conduction spacing under high heart rhythm. Ministry of Economic Affairs Intellectual Property Bureau Xiaogong Consumer Cooperative ip3⁄4 Figure 3 Compounds on the isolated electrical system of the guinea pig negative conductance and coronary vasodilatation; C P F = coronary perfusion, m L = ml. At a heart rate of 300-360 heart beats per minute, compound A with an average concentration of 7 · 7 6 η 产生 produced an average maximum A V interval increase of 23%, resulting in a cardiac septum at an average concentration of 1 · 0 9 η Μ. Under these rhythm conditions, the compound Α produced an increase in the concentration of coronary perfusion, from an average flow rate of 8.5 ml/min to an average flow rate of 14.2 ml/min. The average concentration (E C 5 ) of Compound A which produced a maximum coronary perfusion increase of 50% was 3 2 η Μ. Therefore, Compound A is more than 40 times more effective in slowing A V conduction than increasing coronary perfusion. Detailed description of the preferred embodiment

It has been found that N6 as defined in Formula I above has been replaced by a 5, a (N paper scale applicable to China National Standard (CNS) A4 specification (210X 297 mm) TfZ ~~ 1257306 Ministry of Economic Affairs Intellectual Property Bureau 8 workers consumption Co-op printing A7 B7 V. Inventive Note (6) 〇 Useful compounds include: N6 - cyclopentyl-5'-(N-ethyl)carboxamide adenosine, N6-cyclopentyl-5'-(N -cyclopropyl)carboxamide adenosine, N6 —(3-pentyl)-5'-(N-ethyl)carboxamide gland N6-cyclopentyl-5'-(N-methyl)indole Indole glandular ridge, or N6-cyclopentyl-5'-(N-t-butyl)carboxamide adenosine, and pharmaceutically acceptable salts and esters thereof. The present invention utilizes N 6 of formula I - Substituting a 5'-(N-substituted) carboxyguanamine adenine nucleoside for the treatment of arrhythmia in mammals. Treatment of arrhythmia and random preventive maintenance therapy to minimize recurrence of arrhythmia All should be a useful aspect of the invention. This type of arrhythmia includes supraventricular tachycardia, such as paroxysmal supraventricular tachycardia (PSVT) Atrial fibrillation/jitter (AF). In a preferred aspect of the invention, N 6 - substituted 5'-(N-substituted) carboxyguanamine adenine nucleoside is administered intravenously to about 〇. 〇1 μg/kg to about 1 〇〇μg/kg, preferably about 〇·0 0 5 μg/kg to about 1 μg/kg, more preferably about 〇·0 1 μg/kg to about 〇·5 μg/kg for the treatment of arrhythmia. The infusion time can be determined by the patient. The useful time is from about 2 to about 6 minutes, preferably from about 10 to about 30 minutes. After that, N 6 — Substituted — 5 ' - ( N - substituted) carboxy guanamine adenine nucleoside can be orally administered with appropriate pharmaceutical composition at a dose ranging from about 1 μg/kg to about 10 〇 micro-paper scale for Chinese national standards ( CNS ) A4 size (210X 297 mm) -9 - (Please read the note on the back and fill out this page) 1257306 A7 B7 V. Description of invention (7) g/kg, about 0. 0 1 μg/kg to Preferably, about 1 μg/kg is preferred, and about 0·1 μg/kg to about 8 μg/kg is preferred. The dose is adjusted to the optimum. The patient's response is better. Oral administration is particularly effective in preventive maintenance therapy that minimizes seizures. The optimal dose for intravenous administration is from about 0.1 to about 1 μg/kg/min, and oral administration is optimal. 1 to about 50 μg/kg, up to four times a day as needed. The best compounds for this usage are:

N 6 ; a cyclopentyl-5,-(N-ethyl)carboxamide adenosine, and N 6 1 -cyclopentyl-5,-(N-cyclopropyl)carboxamide adenosine. N 6 5 -cyclopentyl-5, mono(N-ethyl)carboxamide adenosine (a compound of formula I wherein Ri is cyclopentyl and r5 is ethyl) also known as 1-[6-(cyclopentylamine) Base) - 9H - Hip Hop - 9 -yl] - 1 -deoxy-N - Ethyl-1/3 - D-furan ribose decylamine or N 6 -cyclopentyladenosine-5' -ethylcarboxamide . Furthermore, (a) the compound of formula I has been shown to have a function of slowing cardiac pulse conduction as shown by its negative transduction activity and negative shifting activity and (b) hypotensive activity or lack of activity of such a compound Found a difference. Therefore, the dose of these compounds can be adjusted to reduce heart rate to treat arrhythmia without affecting blood pressure. This is a highly desirable property that has not been suggested by prior art. These compounds are expected to have hypotensive activity based on prior art. It was thought that the administration of adenosine A: agonists would aggravate the symptoms of arrhythmia and complicate treatment interventions. It has also been found that the negative allotropic effects of the compounds of formula I vary with the heartbeat. The standard of the paper is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) (please read the note on the back and fill out this page). 装订-----Line of Economics 4^8 workers consumption cooperation 钍 printing 1257306 A7 _ B7 V. Description of the invention (8) When the jump is accelerated, the compound of formula I exhibits a strong ideal negative transduction effect for therapeutic intervention. That is, these compounds are found to be most potent in their therapeutic effects when they are most in need of action (i.e., 'tachycardia tachycardia'). This pharmacological property enables the patient to be administered with the dose of the compound to have no or little effect on the heart under normal conditions, and to exert its therapeutic effect in the case of a rapid heartbeat. The compounds of the present invention can be synthesized according to the methods of U.S. Patent Nos. 5,3,0,7, 3, and 4,8,8,8,106. For example, a compound of formula I can be reacted as an intermediate 6-chloro- 9 with 2',3'-indole-iso-propionyl-inosine-5'-uronic acid with a suitable inorganic acid halide such as sulfinium chloride. [2,3 - oxime-isopropyl propyl-/3-D-ribofuranosyl-5-uronic acid chloride]- 9 Η-嘌呤 synthesized. The intermediate, 6-chloro-9-[2,3-oxime-iso-propyl-hydrazine-D-ribofuranosyl-5-uronic acid chloride]-9 Η-嘌呤, (or its corresponding The bromide 'if the thionyl chloride is replaced by, for example, sulfinium bromide, does not have to be isolated as a pure product. 6-Chloro-9-[2,3-oxan-iso-propyl-/3-D-pyrubonose-5-uronic acid chloride]- 9 Η-嚷呤 acid chloride (or its phase The acid bromide group of the corresponding bromine analog is significantly more susceptible to nucleophile substitution than the 6 position halide of the oxime group. Therefore, according to the process of the present invention, 6-chloro-9-[2,3-oxime-iso-propyl-cold-D-ribofuranosyl-5-uronic acid chloride]-9 Η-嘌呤The first nucleophile of R 1 -Ν 2 reacts to produce a substituted carboxamide intermediate in which the halide is held at the 6 position of the oxime group. Substituted carboxamide intermediates and nucleophiles with formula R2 - ΝΗ2 (please read the notes on the back and fill out this page) - Install. Order ^^^Applicable to Chinese National Standard (〇\'8) 4 specifications (210 father 297 mm) · 1257306 A7 B7 V. Description of invention (9) (Please read the precautions on the back side and then f. This page) Reacts and removes the exo-propyl blocking group to obtain the compound of the present invention. It has a free hydroxyl group at the 2' and 3' positions of the ribofuranosyl group. Instead of the exo-propyl group, other acid-resistant blocking groups can also be used to protect the 2'-OH and 3'-mercapto groups of the ribofuranose group in the reaction step of the inorganic acid halide. The pharmaceutically acceptable salt (water or oil soluble or dispersible form) of the compound of formula I, printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, contains generally non-toxic salts formed, for example, from inorganic or organic acids or bases. The fourth ammonium salt. Examples of such acid addition salts are acetate, adipate, alginate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate, citrate, camphor Acid salt, camphor sulfonate, cyclopentane propionate, diacid salt, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptanoate, glycerol phosphate, hemisulfate, Heptanoate, octanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethylsulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate , nicotine, nitrate, oxalate, pamoate, pectate, persulphate, 3-phenylpropionate, picrate, trimethylacetate, propionate, amber Acid salts, sulfates, tartrates, thiocyanates, benzilates, and "i salts. The salt test includes money salt, metal salt such as sodium and potassium salt, alkaline earth metal salt such as calcium and magnesium salt, organic alkali salt such as dicyclohexylamine salt, N-methyl-D-glucosamine, and amino acid such as fine Salts such as lysine and lysine. Further, the base nitrogen-containing group may be, for example, a lower alkyl halide such as methyl, ethyl, propyl, and butyl chloride, bromide, and iodide; a dialkyl sulfate such as dimethyl, diethyl, Dibutyl; and dipentyl sulfate, long chain halides such as decyl, lauryl, tetradecyl, and stearyl chloride, bromide and iodide, aralkyl halides such as benzene Φ and benzene Ethyl bromide and other forms of the fourth ammonium paper size applicable to the Chinese National Standard (CNS) A4 specifications (2] 0 X 297 mm) 4 1257306 A7 B7 V. Description of the invention (10) Salt. (Please note the following on the back of Mtt, k::·this page) The pharmaceutically acceptable esters of the compounds of formula I contain organic acid esters of the 2' and 3' hydroxyl groups of the ribofuranose group. Preferred ester groups are those which are easily hydrolyzed under physiological conditions. Useful esters include an anthracene group selected from the group consisting of an ethyl group, a propyl group, a butyl group, and a benzamidine group. The invention also contemplates the use of a compound of formula I for the benefit of a mammal to benefit from a negatively variable, negatively variable action, or a combination thereof, to the manufacture of a medicament for treating arrhythmia. The pharmaceutical compositions of the present invention can be administered in any manner that achieves their purpose. For example, administration can be by injection, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular. Alternatively, or in combination with it, you can also wear a mouth. The dose varies with the age, health, and weight of the recipient, depending on the type of treatment, the frequency of treatment, and the nature of the desired effect. The preferred route of administration is intravenous and oral. Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printing Office 5 Because of the danger of heart tissue, it must be effective in the case of arrhythmia. Therefore, intravenous injection is the best route of administration. Intravenous administration can be a single injection, followed by a large number followed by continued administration at a lower maintenance dose, intermittent injections of 'continuous injections at lower doses, or other modes of administration appropriate to the needs of the individual subject. The second preferred route of administration is oral. Certain compounds of the invention have extremely high oral bioavailability. Oral administration is particularly advantageous when a maintenance agent for the compound of the present invention is provided. Since the negative allergic action of the compound of the present invention increases with the increase in heartbeat, the patient can orally receive a therapeutically effective dose when the heartbeat is fast. This paper scale applies to China National Standard (CNS) A4 regulations (2) 0 X 297 mm) 4^--- 1257306 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Μ二Consumer Cooperatives 五5, invention description (11) Pharmacy The formulation is preferably in a unit dosage form. In this form, the preparation is divided into unitary agents each containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged preparation containing a discrete amount of preparation, for example, a packet, a capsule, and a bottle or ampoule powder. The unit dosage form can also be a capsule, a cachet, or nine capsules per se or can be contained in an appropriate amount in the package. The amount of active compound in the unit dosage system can be adjusted from from 1 mg to 1 mg, preferably from 0.1 to 0.5 mg, depending on the particular application and the effectiveness of the active ingredient. The composition may also contain other compatible therapeutic agents if necessary. Examples of useful therapeutic agents that may be administered with the active compound are valpromone, quinidine, procainamide, bisopyramine, florabine, itbufi, toffee, amiodarone , Sutro, sulphur nitrone, Emmono, propranolol, Mido, and Digosin. Furthermore, cardiac arrest and surgical procedures can terminate atrial fibrillation and can be used in the administration of the compounds of the invention. For therapeutic purposes as described above, the dosage range of the sputum animal is from about 0. 00 to about 1 mg/kg body weight per day or preferably about 0. 0 0 for a patient weighing 70 kg. 0 7 to about 0 · 6 mg / kg body weight daily. However, the dosage may vary with the needs of the patient, the severity of the condition, and the compound employed. The determination of the appropriate dose is prior art. Generally, treatment begins with an optimum dose below the compound. Then increase slightly to the optimal dose in this case. For convenience, the daily dose may be administered in divided doses as needed within one day. In addition to the pharmacologically active compound, the new pharmaceutical preparations may contain suitable pharmaceutically acceptable carriers including excipients and adjuvants to facilitate the preparation of the active compound--- Note: Please fill out this page again. The fee is based on the Chinese National Standard (CNS) Α4 specification (210X 297 mm) • 14- 1257306 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5 clothing A7 B7 V. Invention description (12 ) into a pharmaceutically acceptable preparation. The pharmaceutical preparations of the present invention can be produced in a manner known per se, such as the usual mixing, granulating, dragee-making, dissolving, or lyophilization processes. Thus, the oral preparation can be obtained by combining the active compound with a solid excipient, or by honing the mixture, and processing the mixture of granules into a lozenge or a sugar-coated heart after the appropriate adjuvant, if necessary or desired. . Particularly suitable excipients are such as sugars such as saccharides, such as lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate, and binders such as , starch paste, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and / or Polyvinylpyrrolidone. A disintegrating agent such as the above starch and carboxymethyl starch, a crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added as necessary. The adjuvant, in short, is a flow regulating agent and a lubricant such as cerium oxide, talc, stearic acid or a salt thereof such as magnesium stearate or calcium stearate, and/or polyethylene glycol. The sugar coat can be given a suitable coating, if necessary, to resist gastric juice. For this purpose, concentrated sugar solutions may be used, optionally containing gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, a gum solution, and a suitable organic solvent or solvent mixture. For the manufacture of gastric juice resistant coatings, solutions of suitable cellulose preparations, such as ethyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate, may be added to the tablets or coatings with 0 dyes or pigments. For example, identifying or labeling a combination of active ingredients. Other pharmaceutical preparations may contain gelatin capsules for oral administration. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm).

4# 1257306 A7 B7 V. INSTRUCTIONS ((Please first wt* precautions on the back. This page) and soft-sealed capsules made of gelatin and a plasticizer such as glycerin or sorbitol. The capsules may contain or inorganic lactose. a granule-like active compound, such as a binder of starch, and/or a lubricant such as talc or stearyl magnesium, and a random stabilizer. The active compound in the soft capsule is preferably dissolved or suspended. Suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers may be added. Suitable compositions for injection administration include aqueous solutions of water-soluble active compounds, such as water-soluble salts, alkaline solutions and cyclodextrin coordination complexes. One or more of the modified or unaltered cyclodextrins may be used to stabilize the compounds of the present invention and to enhance water solubility. Cyclodextrins useful for this purpose are disclosed in U.S. Patent No. 4,7,27,064. 4,764,604 and 5,0 2 4,9 9 8. The composition for injection can be adjusted to a suitable p 必要 if necessary to provide the highest stability and/or solubility of the active compound. The concentration of the compound of the invention for injecting the composition is from about 0.1 to about 500 micrograms per milliliter, preferably from about 1 to about 250 micrograms per milliliter, and preferably about 5 micrograms. /ml to about 50 μg / ml is more preferred. The injection composition can be liquid, spare composition or lyophilized material, which can be combined before administration. The Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printed, in addition, A suitable oily suspension of the active compound can be administered for injection. Suitable lipophilic solvents or carriers containing a fat oil, such as sesame oil, or a synthetic fatty acid ester such as ethyl oleate or triglyceride or polyethylene glycol-4 0 0 (These compounds are soluble in PEG-400). Aqueous injection suspensions may contain viscosity-enhancing substances such as sodium carboxymethylcellulose, sorbitol, and/or dextrin. This paper scale is applicable to China National Standard (CNS) A4 specification (2J0 X 297 mm) i-cr 1257306 Ministry of Economic Affairs Intellectual Property Office Completion Consumer Cooperative Printing A7 _B7 V. Invention Description (14) Examples The following examples For explanation, not for The method and composition of the present invention are well modified and transformed by the conditions and parameters commonly encountered by those skilled in the art. The concentration dose data is returned to the S-shaped curve by Graphpad PRIZMtm software. Determine the concentration of the test compound on the adenosine A i receptor to produce 50% of the maximum available response or the dose of E C5 in the test tube or the ED 5 in the living body. The measured response to each dose The sputum squirrel was only spiked with the test compound accumulating in the isolated left atrium to attenuate the contractile energy response to the plateau and to respond to rapid intravenous bolus of the test compound. Oral bioavailability is estimated from the pharmacodynamic response using the following: (reaction AUC. "! / reaction AUCiv) (dose iv / dose. rai ), where reaction a UC is the slow pulse versus time induced by the test reagent The area under the curve. Example 1 In-tube activity The male Spitzer-type pottery with a weight of 200 to 350 g was quickly taken out and placed in a warmed Kexian buffer after sacrifice. The left atrium was suspended from a 30 ml jacket in an organ bath isolated from the heart, and was filled with kexian buffer and oxygenated at 9 5 % 0 2 / 5 % C〇2 and maintained at 3 7 °. C. Attach the tissue to the force displacement sensor at 1 gram of closed tension. The extra-large voltage of 1 Hz and 1 millisecond is used as the electrical stimulation of the atrium to produce a regular contraction of the tissue. Add adenosine A 1 agonist to the bath to increase the cumulative concentration to obtain contractility - (Please read the back note first and then fill out this page)

, 1T .4 This paper scale applies to China National Standard (CNS) Α 4 specifications (210X29*7 mm) -17- 1257306 A7 B7 Ministry of Economic Affairs Smart Finance 4 Bureau 8 2 Elimination Cooperative System 5, Invention Description (16) These The data shows that this series of compounds is potent in the in vitro test of the adenoid A1 receptor. Example 2 In vivo activity of male and female cockroaches-potent rats was anesthetized with 50 mg/kg of intraperitoneal pentobarbital sodium, and surgically implanted into the carotid artery and jugular vein, two days before each experiment. get on. All subsequent experiments were awakened and unaccepted. The carotid catheter was connected to a pressure transducer and blood pressure was continuously recorded using a Gurstot trace. The heartbeat is derived from the blood pressure signal using the Glass tachycardia. The measurement parameters are stabilized for 30 to 90 minutes before the test compound is administered. The test compound is administered by means of a curved or blister oral dose cannula for oral feeding or via a jugular vein into a catheter for intravenous administration. Oral rats are fasted overnight before the administration, and only water is supplied. Because the heartbeat response quickly returns to baseline after intravenous administration of the test compound, each mouse can be given more than one dose of the test compound. However, the response of the oral test compound can only be given to a single dose per mouse. The comparison of the area under the slow pulse versus time curve (A U C ) after intravenous and oral administration is used as a scale for oral bioavailability. The results are shown in the table below:

R1 I NH

This paper scale applies to China National Standard (CN'S) A4 specification (210X297 mm) -19- (Please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau g (Working Consumer Cooperative System 1257306 A7 _B7_5 , invention description (18) for the measurement of atrial ventricular (AV) conduction. Compound A produces a concentration-dependent AV conduction slowdown 'Maximum S-V interval increase occurs at an average concentration of 6 · 8 η Μ and AV conduction partition occurs on average Concentration 8 · 3 η Μ. At these concentrations, Compound A has no effect on coronary blood flow. This shows that Compound A is a potent adenosine A: receptor agonist, which induces a great dose without affecting coronary dilation. Negatively variable effect. Example 4 The difference between negative shifting activity and hypotensive activity. On the second day before the experiment, the male Shigege-Taoli mouse was anesthetized with 50 mg/kg, intraperitoneal pentobarbital sodium. The carotid artery and jugular vein were surgically implanted into the catheter. In all subsequent experiments, the rats were only awakened and untreated. The carotid catheter was connected to the pressure sensor, and the blood pressure was continuously recorded by Grasto. The heartbeat was stimulated with Glass. The velocity map is derived from the blood pressure signal. The measurement parameters are stabilized at 30 to 90 minutes prior to administration of the test drug. Compound A is placed in the jugular vein via a jugular vein for intravenous administration or a curved or blister oral dose cannula for oral administration. Feeding. Food and water were supplied arbitrarily. The ED 5 ^ inducing the slow pulse was found to be 0 · 1 μg / kg / min in the intravenous mode for 120 minutes, resulting in an average of 34% of the heartbeat slowed down and the average blood pressure did not change. Intravenous dose 〇·〇5 μg/kg/min to 0.1 μm/kg/min showed no change in blood pressure. Similarly, 'oral dose of 30 μg/kg to 1 〇〇μg/kg does not change blood pressure, 1 0 0 micrograms/kg results in an average of 40% of heartbeat acceleration. This display - clothing - (please read the note on the back and fill out this page) - the standard paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 public) PCT) -21 - 1257306 Α7 ____ Β7 ___ V. INSTRUCTIONS (19) When the compound in the example has a very significant negative shifting effect, its dose has no effect on blood pressure. (Please read the note on the back and then on: this page) Example 5 Negative change of self-jumping heart And the display of the negative shifting activity, the Erlangendorf method prepares the guinea pig to separate the heart and its coronary vasculature is perfused through the aorta in a retrograde manner. Compound A is infused through a perfusion line supplying the buffer to the coronary vasculature. The concentration of Compound A in the perfusate was calculated by dividing the infusion rate of Compound A by the coronary blood flow. The self-jumping heartbeat and AV interval were recorded. The experimental results are shown in Figure 1. Compound A production is dependent on concentration. The slowing of AV conduction, the maximum increase in AV interval represents an increase of 3.4% from the base. Compound A also produces a concentration-dependent heartbeat deceleration, E C 5 .値 is .3. · 2 η Μ and the maximum heart rate is slowed down to 58%. Example 6 Display of the effect of heartbeat on negative transduction activity The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed 4'J Clothes Prepare the separated scorpion heart according to the method of Example 5. Before the half-experiment was designed to determine the effect of the heartbeat on the negative transduction activity of Compound A, the rat heart was allowed to self-jump or to electrify at 2 〇0 per minute (about 20% higher than self-jump) or per minute. 3 0 0 to 3 6 0 (about 80% higher than self-jump). The atrial ventricular (A V ) conduction interval (A V interval) was measured from atrial stimulation to ventricular depolarization time. As in Example 5, the measurement of the A V interval was carried out under the law of the increase in the concentration of the compound A. The whole law is 2 每 per minute 〇 too paper ruler applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1257306

A B 5. In the invention description (2Q), the compound A with an average concentration of 3 · 9 η 产生 produces an average maximum 580% increase in the A V interval' and a cardiac partition at the average minimum concentration of 5.1 η Μ. When the electrical law is from 300 to 6,000 per minute, the compound Α produces an average maximum of 20% increase in the AV interval at an average concentration of 1 · 4 5 η ,, and the average minimum concentration of 2. 1 η Μ leads to a heart cut off. The above results are summarized in the table below, including self-jumping data for comparison: (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Smart Assets 4 Employees' Cooperatives Print These data show the compounds produced in the examples The negative conductance depends on the heartbeat, and the rhythm is accelerated, and the compound A shows the effect of ascending. Example 7 The negative transduction activity of the experimental model of paroxysmal supraventricular tachycardia was shown by the experimental conditions of Example 6, the individual heart rhythm was at 200 bmp - min and then the rhythm was 3 0 0 bmp After that, the whole law returns 2 0 0 bmp. This 3 0 b m p rhythm is used to simulate the onset of supraventricular tachycardia. The rhythm sequence is carried out in a vehicle at a concentration in which the compound is increased. The results are shown in Figure 2. The average average concentration (nM) of Compound A of Compound A at the average concentration of heartbeat (bpm) to produce a large AV interval to produce a cardiac septum required. Small concentration (nm) Self-jumping 11.7 13 (about 170) 200 3.9 5.1 300 to 360 1.45 2.1 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X29? mm) 1257306 A7 B7 V. Invention description (21) 2 η Μ has little effect on the AV interval of 200 bmp, The AV partition was induced in 30 seconds during the 300 bmp period. When the rhythm returns to 2 0 0 b m ρ, the A V interval also returns to near normal 値. Example 8 The difference between the negative shifting activity of the heart and the coronary dilatation is to determine the differential effect of the negative shifting activity of Compound A on the coronary artery expansion in the heart of the heart. Another set of experiments was performed in which individual effects were collected by individual hearts. Measurement. Using the experimental conditions of Example 6, the guinea pig was isolated from heart to heart at 300 to 360. The A V conduction interval was measured as in Example 6. The volume of fluid flowing out of the heart was measured to determine coronary perfusion data. A V conduction interval data and coronary perfusion data were collected at increasing concentrations of Compound A. The results are shown in Figure 3, where there is a dose-related A V conduction interval and an increase in coronary perfusion. The difference in these effects is evident. The average concentration of Compound A which produced a significant increase in A V conduction time was 〇 · 7 6 η Μ. The concentration of the compound that produces a semi-maximal effect of coronary perfusion (E C5 〇 is 3 2 η Μ. The compound Α slows the AV conduction time by more than 40 times stronger than the increase of coronary perfusion. The invention has been described in detail thus far. It should be understood by those skilled in the art that the invention can be practiced in a broad and equivalent range of conditions, formulas, and other parameters without affecting the field of the invention or any embodiments thereof. All patents, patent applications cited herein And the literature is completely imported for reference. (Please read the notes on the back and fill out this page) • Installed and subscribed to the Ministry of Economic Affairs, Intellectual Property Bureau, employees, bone-dissipation cooperatives, printed paper scale applicable to China National Standard (CNS) A4 specifications (210X 297 mm) -24-

Claims (1)

A8 B8 C8 D8 1257306 No. 89 12429 Patent application No. 1 Patent application scope 丨 Replacement of the Republic of China on January 17, 1994 Revision 1. A method for treating arrhythmia in humans in need of treatment and facilitating the induction of negative transduction and/or negative shifting A pharmaceutically active composition comprising an effective amount of a compound of the formula: R1 I NH (Please read the precautions on the back and fill out this page.) Pack - The salt or ester printed or pharmaceutically acceptable by the Consumers' Cooperatives of the Ministry of Economic Affairs; 1^(:3-7 second alkane a group, or a C3-8 cycloalkyl group; and a 112 line (: 1-3 alkyl group, Ci-3 hydroxyalkyl group or C3-5 cycloalkyl group, wherein the dose is from 0 001 to 'can produce the desired treatment The effect does not significantly affect the blood pressure and/or has a slight or no effect on the heart under normal conditions. 2. The pharmaceutical composition of claim 1, wherein: R i is 3-pentyl a cyclopentyl group or a reduced-fat group, and R2 is a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group. 3. The pharmaceutical composition according to claim 1 of the patent application, which is administered in a parenteral form. This paper scale applies to the Chinese National Alignment (CNS) A4 specification (21〇X 297 嫠) [257306 A8 B8 C8 D8 pharmaceutical composition, its system is static, patent application scope 4 · If the patent application scope Injection. The pharmaceutical composition of claim 1 is an oral dosage form. The pharmaceutical composition of the first aspect, wherein the R 2 is an ethyl hydrazone, the pharmaceutical composition of the first aspect of the invention, wherein the R 2 is a cyclopropyl group. The pharmaceutically acceptable composition of the first aspect of the invention, wherein R: is a cyclopentyl group. 1 〇 The pharmaceutical composition of claim 1, wherein R A pharmaceutical composition according to the first aspect of the invention, wherein the R 2 is a cyclopropyl group. The pharmaceutical composition according to claim 4, wherein the compound is selected from the group consisting of: N6-cyclopentyl-5'-(N-ethyl)carboxamide Adenine nucleus N6-cyclopentyl-5'-(N-cyclopropyl)carboxamide Adenine N6 —(3 -Pentyl)- 5'-(N-ethyl)carboxamide adenine nucleoside, and (please read the back note first and then fill out this page) The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed too Secrets · 4* On / /-«xtc \ k λ / λιλ, / Bazheng \ 1257306 A8 B8 C8 D8 VI. Patent application scope N a ring a 5-'-(N-methyl)carboxamide adenine nucleocapsid, and a pharmaceutically acceptable salt thereof and an ester thereof. The pharmaceutical composition of claim 4, wherein the compound N6~(3-pentyl)-5, (N-ethyl)carboxamide adenine nucleoside. 1 4 The pharmaceutical composition of claim 3, wherein the hydration system N 〜 Cyclopentyl-5'-(N-ethyl) residue adenine 嘿 令 nucleus has 1 〇1 5 · The pharmaceutical composition of claim 3, wherein the compound is N6-cyclopentyl-5 'A (N-cyclopropyl) carboxamide adenine nucleoside. The pharmaceutical composition of claim 5, wherein the compound is N6-cyclopentyl-5'-(N-ethyl)carboxamide adenine nucleoside. The pharmaceutical composition of claim 5, wherein the compound is N6-cyclopentyl-5, (N-cyclopropyl)carboxamide glandamine. 1 8 The pharmaceutical composition of claim 1, wherein the cardiac rhythm is a systemic supraventricular tachycardia. 1 9 The pharmaceutical composition of claim 1, wherein the heart rhythm is a paroxysmal supraventricular tachycardia. A pharmaceutical composition according to claim 1, wherein the arrhythmia is atrial fibrillation. This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) ---------- (Please read the note on the back and fill out this page) Lm, Ministry of Economic Affairs Intellectual Property Office staff Consumer Cooperatives Printed 1257306 A8 B8 C8 D8 ", Patent Application No. 2 1 · The pharmaceutical composition of claim 5, which is an oral form, and its dosage is from about 1 to about 50 micrograms per kilogram of body weight. 2 2 · The pharmaceutical composition according to item 3 of the patent application is static and the amount is from about 0.1 to about 10 μg/kg/min infusion bell. 2 3 skin is taken. 2 4 cheek 2 5 The pharmaceutical composition of claim 1 is a pharmaceutical composition as claimed in item i of the patent application, which is the basis (please read the note on the back of the tt and then fill in the page) C - The Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs prints the pharmaceutical composition as claimed in item 3 of the patent application, which is administered intravenously, and the amount of the compound is from about 微. 〇〇1 μg/kg to about 1 0 0 μg / kg. 2 6 · Pharmaceutical group as claimed in item 25 And the amount of the compound is from about 5 μg/kg to about 1 μg/kg. 2 7 · The pharmaceutical composition of claim 26, wherein the amount of the compound is from about 〇·〇 1 μg/kg to about 微·5 μg/kg. 2 8 · The pharmaceutical composition according to any one of claims 3, 25, 26 and 27, which is about 2 to about 60 In the case of the pharmaceutical composition of claim 28, the pharmaceutical composition is administered at intervals of about 10 to about 30 minutes. 3 0 Pharmacy as claimed in claim 4 The composition is applied to the Chinese National Standard (CNS) A4 specification (210X297 mm) - 1257306 A8 B8 C8 D8. The patent application scope is intravenously administered, and the dosage of the compound is self-administered. From about 0.1 μg/kg/min to about 10 μg/kg/min. 3 1 · The pharmaceutical composition of claim 5, wherein the Qi! I i is from about 〇·〇〇i microgram/kg To about i 〇〇 micrograms/kg 〇 3 2 · as pharmacy composition of claim 31, The dose is from about 1 μg/kg to about 1 μg/kg. 3 3 · The pharmaceutical composition of claim 32, wherein the dose is from about 微·1 μg/kg to about 8 μg / kg. 3 4 · If you apply for the pharmacy composition of item 21 of the patent scope, it will be given up to 4 times per 。. --------0^ II (Please read the back of the note first) Please fill out this page again. The Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumer Cooperatives, Printed Paper Size, China National Standard (CNS) A4 Specification (210X297 mm)