JP2003514863A - Treatment of heart rhythm disorders with N6-substituted 5 '-(N-substituted) carboxamide adenosine - Google Patents

Abstract

(57) Abstract: The present invention is a cardiac rhythm disorder in a mammal in need of treatment a cardiac rhythm disorders, N ^{6-substituted-5} '- methods for treating by administration of (N- substituted) carboxamides adenosine Disclose. More particularly, the present invention relates to a method for the treatment of a heart rhythm disorder in a mammal that would benefit from the induction of a negative conducting and / or negative chronotropic effect, the method comprising the following formula (I) ): Or administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, wherein R ¹ is C _3-7 secondary alkyl or C _3-8 cycloalkyl. And R ² is C _1-4 alkyl or C _3-5 cycloalkyl. The present invention also relates to novel dosage forms containing the above compounds.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to cardiac rhythm disorders in mammals of certain adenosine A ₁ agonists belonging to the class of N ⁶ -substituted-5 ′-(N-substituted) carboxamide adenosine. In the treatment of, and new dosage forms for implementing this new use.

Related Art [0002] In the mammalian heart, the contraction of the ventricles causes the sinoatrial (SA) to circulate blood.
Initiated by an electrical impulse in the nodule, which then passes through the atrioventricular (AV) node to the ventricles. A consistent rhythmic impulse produces a regular heartbeat when the heart functions normally.

Various dysfunctions can occur in the heart, disrupting the regular heartbeat pattern and producing arrhythmias. For example, an overly rapid heartbeat condition, defined as tachycardia, can occur. Tachycardia is an excessively rapid release from dysfunctional SA nodules, an accessory pathway that promotes beats before they normally occur.
It can result from electrical impulses passing through y) or reentry of impulses at the AV node. In such cases, the disorder is referred to as paroxysmal supraventricular tachycardia (PSVT), which in some patients can progress to congestive heart failure. Another cardiac rhythm disorder called atrial fibrillation / flutter (AF) is characterized by rapid and disturbed atrial beats and is associated with increased seizure rates. The above cardiac rhythm disorders can be classified as supraventricular tachyarrhythmias. Symptoms of these disorders include palpitation,
Fatigue, discomfort due to dyspnea, and lightheadedness
and / or the perception of dizziness.

Adenosine is well known to slow the heart rate (negative chronotropic effect) and slow impulse conduction through the AV node (negative chronotropic effect) (Berne et al., US Pat. No. 1). 4,673,563; Belardinell
i et al., Journal of Pharmacology and Expert.
(Thermal Therapeutics 271: 1371 (1994))
. Adenosine is currently used in the treatment of PSVT, but has not been shown to be effective in converting AF to normal sinus rhythm.

Adenosine acts through multiple receptor subtypes termed A ₁ , A _2A , A _2B and A ₃ . The adenosine A ₁ receptor mediates the negative chronotropic and negative dromotropic effects of adenosine and directly suppresses atrial contractility (
However, it does not suppress ventricular contractility). The adenosine A _2A receptor mediates the action of adenosine to dilate the coronary arteries. The localization and function of the adenosine A _2B and adenosine A ₃ receptors in the heart is not well defined.

One strategy for terminating PSVT is that PSVT can result from abnormally frequent impulses affecting the AV node, and the adenosine A ₁ receptor mediates the negative transconducting effects of adenosine. To slow down impulse conduction through the AV node using a selective adenosine A ₁ receptor agonist (Belardinelli et al., Journal of Pha.
rmacology and Experimental Therapeut
ics 271: 1371 (1994); Snowdy et al., British J.
individual of Pharmacology 126: 137 (1999)
).

However, the adenosine A ₁ receptor agonists that have been studied to this end have lacked the required potency, selectivity, oral bioavailability and / or pharmacodynamic activity. Moreover, prior art adenosine A ₁ agonists have also been shown to be hypotensive. Being hypotensive is a side effect that exacerbates the symptoms of patients who have experienced cardiac rhythm disorders.

A series of N ⁶ -substituted-5 ′-(N-substituted) carboxamide adenosine derivatives are:
It has been previously described. These compounds are selective adenosine A ₁ receptor agonists (Olsson, R. and Thompson, R., US Pat. No. 5,310,731) and have utility as vasodilators or antihypertensive agents.

SUMMARY OF THE INVENTION The present invention relates to a method for the treatment of cardiac rhythm disorders in a mammal that would benefit from the induction of a negative dromotropic effect, a negative chronotropic effect or a combination thereof. An effective amount of a compound of formula I below:

[0010]

[Chemical 4] Or administering a pharmaceutically acceptable salt or ester thereof to a mammal in need of such treatment; wherein R ₁ is C _3-7 secondary alkyl, or C _3-8 Is cycloalkyl; and R ₂ is C _1-4 alkyl, C _1-4 hydroxyalkyl or C _3-5 cycloalkyl.

Such cardiac rhythm disorders include supraventricular tachyarrhythmias (eg, paroxysmal supraventricular tachycardia (PSVT) and atrial fibrillation / flutter (AF)).

The present invention also relates to novel intravenous and oral dosage forms, which contain specific concentrations of one or more compounds of formula I.

The present invention also relates to the use of a compound of formula I in the manufacture of a medicament for treating a cardiac rhythm disorder in a mammal that would benefit from the induction of negative dromotropic effects, negative chronotropic effects or a combination thereof. .

Detailed Description of the Preferred Embodiments Certain N ⁶ -substituted-5 ′-(N-substituted) carboxamide adenosines defined by Formula I above are particularly desirable pharmacology useful in the treatment of cardiac rhythm disorders. It has been found here to have specific properties. These compounds possess one or more of unexpected potency, selectivity, oral bioavailability and pharmacodynamic activity.

Accordingly, the present invention relates to a method for the treatment of cardiac rhythm disorders in a mammal that would benefit from the induction of a negative chronotropic effect, a negative chronotropic effect, or a combination thereof, the method comprising: The following compounds of formula I:

[0016]

[Chemical 5] Or administering a pharmaceutically acceptable salt or ester thereof to a mammal in need of such treatment; wherein R ₁ is C _3-7 secondary alkyl, or C _3-8 Is cycloalkyl; and R ₂ is C _1-4 alkyl, C _1-4 hydroxyalkyl or C _3-5 cycloalkyl.

Useful values of R ₁ include isopropyl, 2-butyl, 2-
Mention may be made of pentyl, 3-pentyl, 2-hexyl, 3-hexyl, 2-heptyl, 3-heptyl, 4-heptyl, cyclopropyl, cyclopentyl, cyclohenyl, cycloheptyl and norbornyl. Preferred groups for R ₁ include 3-
Pentyl, cyclopentyl or norbornyl, more preferably 3-pentyl or cyclopentyl can be mentioned. Useful groups for R ₂ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl and cyclopentyl. Preferred groups for R ₂ are methyl, ethyl, hydroxyethyl, isopropyl or cyclopropyl,
More preferably, ethyl or cyclopropyl is mentioned.

Useful compounds include: N ⁶ -cyclopentyl-5 ′-(N
- ethyl) carboxamide adenosine, N ⁶ - cyclopentyl-5 '- (N-cyclopropyl) carboxamide adenosine, N ⁶ - (3- pentyl) -5' - (
N- ethyl) carboxamide adenosine, N ⁶ - cyclopentyl -5 '- (N-
Methyl) carboxamido adenosine or N ⁶ -cyclopentyl-5 ′-(N-
t-Butyl) carboxamidoadenosine, and pharmaceutically acceptable salts and esters thereof.

The present invention provides a N ⁶ -substitution of formula I-for treating cardiac rhythm disorders in a mammal.
Administration of 5 '-(N-substituted) carboxamide adenosine is utilized. Both treatment of episodes of cardiac rhythm disorders and any preventative maintenance therapy that minimizes future occurrences of cardiac rhythm disorders are contemplated as useful aspects of the invention. Such cardiac rhythm disorders include supraventricular tachyarrhythmias (eg, paroxysmal supraventricular tachycardia (PSVT) and atrial fibrillation / flutter (AF)).

In a preferred aspect of the invention, the N ⁶ substituted-5 ′-(N-substituted) carboxamidoadenosine is from about 0.001 μg / kg to about 100 μg / kg, preferably about 0.
005 μg / kg to about 1 μg / kg, more preferably about 0.01 μg / kg to about 0.5 μg / kg is administered by intravenous infusion to treat a cardiac rhythm disorder. The duration of this infusion can be adjusted for individual patients. A useful infusion period is about 2 minutes to about 60 minutes, preferably about 10 minutes to about 30 minutes. Thereafter, N ⁶ -substituted-5 ′-(N-substituted) carboxamidoadenosine is optionally added in an amount of about 0.001 μg / kg to about 100 μg / kg, preferably about 0.01 μg / kg
kg to about 10 μg / kg, more preferably about 0.1 μg / kg to about 8 μg / kg
Can be administered orally in a suitable pharmaceutical composition at a dose within the range of This dose is preferably adjusted to optimize the individual patient response. Oral administration is particularly useful as a preventative maintenance treatment to minimize the episodic occurrence of these cardiac rhythm disorders.

The most preferred dose administered intravenously is from about 0.1 μg / kg / min to about 10 μg.
/ Kg / min, while the most preferred dose administered orally is, if desired,
It is about 1 μg / kg to about 50 μg / kg up to 4 times a day.

The most preferred compounds for this utility are: N ⁶ -cyclopentyl-5 ′-(N-ethyl) carboxamide adenosine and N ⁶ -cyclopentyl-5 ′-(N-cyclopropyl) carboxamide adenosine. . N ⁶ -Cyclopentyl-5 ′-(N-ethyl) carboxamido adenosine (a compound of formula I where R ₁ is cyclopentyl and R ₂ is ethyl) also includes 1- [6- (cyclopentylamino) -9H. It is also known as -purin-9-yl] -1-deoxy-N-ethyl-β-D-ribofuranuronamide or N ⁶ -cyclopentyladenosine-5′-ethylcarboxamide.

Further, (a) the compound of formula I slows impulse conduction in the heart as evidenced by its negative and chronotropic activity, as compared to (b) below. It has been found that there is a gap between capacity and (b) hypotensive activity or lack thereof for such compounds. Thus, these compounds may be administered in a manner to treat heart rhythm disorders by reducing heart rate without affecting blood pressure. This is a highly desirable property that has not been suggested by the prior art. Based on the prior art, these compounds are expected to have hypotensive activity. It is expected that the administration of adenosine A ₁ agonists will worsen the symptoms of patients experiencing cardiac rhythm disorders and complicate therapeutic intervention.

It has been found that the negative transconducting effect of compounds of formula I is heart rate dependent. As the heart rate increases, the compounds of formula I show an increased ability in producing the desired negative transconductance effect used in therapeutic intervention. That is, it was found that these compounds exert their therapeutic effect most strongly against the condition where this effect is most needed (ie tachycardia). This pharmacological profile shows these compounds at a level such that under normal conditions minimal or no effect on the heart, but under abnormal conditions of excessively rapid heartbeat, therapeutic effects are exerted. Provides the option to administer to the patient.

The compounds of the present invention are disclosed in US Pat. Nos. 5,310,731 and 4,868,
It can be synthesized according to the method described in No. 160. For example, a compound of formula I may be treated with a suitable inorganic acid halide (eg, thionyl chloride) to give a 2 ', 3'.
Intermediate 6-obtained from -O-isopropylidene inosine-5'-uronic acid
Chloro-9- [2,3-O-isopropylidene-β-D-ribofuranosyl-5-
Uronic acid chloride] -9H-purine may be obtained. This intermediate 6-chloro-9-
[2,3-O-isopropylidene-β-D-ribofuranosyl-5-uronic acid chloride] -9H-purine (or the corresponding bromide, for example, when thionyl bromide is used instead of thionyl chloride) is pure It does not need to be isolated in a stable state.

Acid chloride moiety of 6-chloro-9- [2,3-O-isopropylidene-β-D-ribofuranosyl-5-uronic acid chloride] -9H-purine (or the acid bromide of the corresponding bromo analog). Is replaced by a nucleophile at position 6 of the purine moiety significantly more easily than a halide group. Therefore, according to the process of the present invention, 6-chloro-9- [2,3-O-isopropylidene-β-D-ribofuranosyl-5-uronic acid chloride] -9H-purine was prepared according to the formula R ₁ -NH ₂ . Reaction with the first nucleophile possesses affords the intermediate substituted carboxamide where the halide is retained at the 6 position of the purine moiety.

This intermediate, a substituted carboxamide, is subsequently reacted with a nucleophile having the formula R ₂ —NH ₂ and the isopropylidene blocking group removed with acid to remove the 2 of the ribofuranose moiety. Compounds of the invention having free hydroxyl groups in the 'and 3'positions are obtained. Instead of the isopropylidene blocking group, other acid stable blocking groups may also be used to protect the 2'-OH and 3'-OH groups of the ribofuranose moiety during the treatment step with the inorganic acid halide.

Pharmaceutically acceptable salts of the compounds of formula I (in the form of water-soluble or oil-soluble or water-dispersible or oil-dispersible products) are formed, for example, from inorganic or organic acids or bases. Conventional non-toxic salts or quaternary ammonium salts. Examples of such acid addition salts include: Acetate,
Adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate. , Heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate. , Picrate, pivalate, propionate, succinate Sulfate, tartrate, thiocyanate, tosylate, and undecanoate. Basic salts include the following: ammonium salts, alkali metal salts (eg sodium salts and potassium salts), alkaline earth metal salts (eg calcium salts and magnesium salts), salts with organic bases (eg Dicyclohexylamine salts, salts with N-methyl-D-glucamine and amino acids (eg, arginine, lysine)) and the like. Further, the basic nitrogen-containing group is a lower alkyl halide (for example, methyl chloride, ethyl chloride, propyl chloride and butyl chloride, methyl bromide, ethyl bromide, propyl bromide and butyl bromide and methyl iodide, ethyl iodide, propyl iodide and butyl iodide); Dialkyl sulfate (eg, dimethyl,
Diethyl, dibutyl); and diamyl sulfate, long-chain halides (eg, decyl chloride, lauryl chloride, myristyl chloride and stearyl chloride, decyl bromide, lauryl bromide, myristyl bromide and stearyl bromide, and decyl iodide, lauryl iodide, myristyl iodide). And stearyl iodide), aralkyl halides such as benzyl bromide and phenethyl bromide, and the like.

Pharmaceutically acceptable esters of compounds of formula I include organic acid esters of hydroxyl groups at the 2 ′ and 3 ′ positions of the ribofuranose moiety. Ester groups are preferably a class of groups that are relatively easily hydrolyzed under physiological conditions. Useful esters include those having an acyl group selected from the group consisting of acetyl, propionyl, butyryl and benzoyl groups.

The present invention also relates to the use of a compound of formula I in the manufacture of a medicament for treating a cardiac rhythm disorder in a mammal that would benefit from the induction of negative dromotropic effects, negative chronotropic effects or a combination thereof. .

The pharmaceutical composition of the invention may be administered by any means that achieves its intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular routes. Alternatively, or concurrently, administration can be by the oral route. The dosage administered will be dependent on the age, health and weight of the recipient, the current type of treatment, if any, frequency of treatment and the nature of the effect desired. The preferred routes of administration are intravenous injection and oral administration.

There may be a danger to heart tissue, so there is a need for rapid onset of action in conditions of cardiac rhythm disorders. Thus, intravenous injection is the first preferred route of administration. Intravenous administration may be a single injection, a loading dose, followed by continuous administration of lower levels of maintenance dose, injections at regular intervals of time, continuous injection of low levels of maintenance dose, or of the individual being treated. It may consist of other types of administration as appropriate to the needs.

The second preferred route of administration is oral administration. Certain compounds of the invention have very high oral bioavailability. Oral administration is a particularly useful route to provide maintenance doses of the compounds of the invention. Since the negative transduction effect of the compounds of the invention increases with increasing heart rate, patients may receive an oral dose that exerts a therapeutic effect if the heart rate becomes too rapid.

Preferably the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these in packaged form.

The amount of active compound in a unit dose preparation may be varied or adjusted from 0.01 mg to 1 mg, preferably 0.1 mg to 0.5 mg, according to the particular application and potency of the active ingredient. The composition can, if desired, also contain other compatible therapeutic agents.
Examples of useful therapeutic agents that may be co-administered with the active compounds of the present invention include verapamil, quinidine, procainamide, diisopyramide.
), Flecanide, ibutilide,
Examples include dofetilide, amiodarone, sotalol, diltiazem, esmolol, propranolol, metoprolol and digoxin. In addition, DC cardioversion and surgical procedures are available to terminate atrial fibrillation and can be used in combination with administration of the compounds of the invention.

In the above therapeutic applications, the mammalian dosage range for a 70 kg subject is from about 0.00035 mg / kg body weight / day to about 1 mg / kg body weight / day, or preferably about 0.0007 mg. / Kg body weight / day to about 0.6 mg / kg body weight /
Is the day. However, the dosage may vary depending on the requirements of the patient, the severity of the condition to be treated and the compound used.

Determination of the proper dosage for a particular situation is within the skill of the art.
Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions daily, if desired.

In addition to the pharmacologically active compound, the new pharmaceutical preparations can be prepared with suitable pharmaceutically acceptable carriers which facilitate the processing of the active compound into pharmaceutically usable preparations. (Including excipients and auxiliaries).

The pharmaceutical preparations according to the invention are produced in a manner known per se, for example by conventional mixing, granulating, dragee-making, dissolving or lyophilizing processes. Therefore, pharmaceutical preparations for oral use may be prepared by combining the active compound with solid excipients, adding suitable auxiliaries if desired or necessary, and then milling the resulting mixture, if necessary. And processing the mixture of granules to obtain tablets or dragee cores.

Suitable excipients are in particular fillers such as sugars (eg lactose or sucrose), mannitol or sorbitol, cellulose preparations and / or calcium phosphates (eg tricalcium phosphate or calcium hydrogen phosphate), And binders (eg corn starch, wheat starch, rice starch, potato starch, eg starch paste, gelatine, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone). If desired, disintegrating agents may be added, such as the starches described above, and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or salts thereof (eg sodium alginate). Auxiliaries are, above all, flow regulators and lubricants (for example silica, talc, stearic acid or its salts (for example magnesium stearate or calcium stearate) and / or polyethylene glycol). Dragee pill cores are provided with suitable coatings that, if desired, are resistant to gastric juices. For this purpose concentrated sugar solutions may be used, which may, if desired, be gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvents. It may include a mixture. A solution of a suitable cellulose preparation (eg, acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate) is used to produce a coating resistant to gastric juices. Dyestuffs or pigments may be added to the tablets or dragee coatings, for example for identification of the active compound dose or for characterizing the active compound dose combination.

Other pharmaceutical preparations that can be used orally include push fit capsules made of gelatin, as well as made of gelatin and a plasticizer such as glycerol or sorbitol and sealed. Examples include soft capsules. Press-fit capsules are in the form of granules that can be mixed with fillers (eg lactose), binders (eg starch) and / or lubricants (eg talc or magnesium stearate) and optionally stabilizers. Active compounds of In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers can be added.

Formulations suitable for parenteral administration include aqueous solutions of the active compounds in water-soluble form (eg, water-soluble salts, alkaline solutions and cyclodextrin inclusion complex). One or more modified or unmodified cyclodextrins can be used to stabilize and increase the water solubility of the compounds of the invention. Cyclodextrins useful for this purpose are disclosed in US Pat. Nos. 4,727,064, 4,764,604 and 5,024,998. Formulations suitable for parenteral administration may be adjusted, if necessary, to the appropriate pH to provide maximum stability and / or solubility for the active compound. The tonicity of such formulations can be adjusted using known tonicity adjusting agents. The concentration of active agent in the parenteral formulations of the invention is from about 0.1 μg / mL to about 500 μg / mL, preferably from about 1 μg / mL to about 2.
50 μg / mL, and more preferably about 5 μg / mL to about 50 μg / mL. Parenteral formulations can be liquid, ready-to-use formulations or lyophilizates that can be reconstituted prior to administration.

Additionally, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles are fatty oils (eg sesame oil) or synthetic fatty acid esters (eg ethyl oleate or triglycerides) or polyethylene glycol-400 (this compound is soluble in PEG-400). Can be mentioned. Aqueous injection suspensions may, for example, contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol and / or dextran. The suspension, if desired, can also contain stabilizers.

EXAMPLES The following examples are illustrative of the methods and compositions of the present invention, but do not limit the methods and compositions of the present invention. Appropriate modifications and adaptations of the various conditions and parameters normally encountered and apparent to those skilled in the art are within the spirit and scope of the invention.

Concentration dose-effect curve data was fit to a sigmoidal curve using Graphpad PRIZM ^™ software to produce 50% of the maximal achievable response of adenosine A ₁ receptor activation to test compound concentration or test. Compound doses (in vitro EC ₅₀ values or in vivo ED ₅₀ values) were obtained. The response measured for each dose was cumulative addition of the test compound in the isolated left atrium, and negative muscle plateau to peak bradycardia upon bolus intravenous injection of the test compound in conscious rats. It was an inotropic response. Oral bioavailability was estimated from the pharmacodynamic response using the following expression: (Response AUC _oral / Response AUC _intravenous ) (
Dose _intravenous / dose _oral ), where the response AUC is the area under the curve for test compound-induced bradycardia over time.

Example 1 In Vitro Activity Male Sprague-Dawley rats weighing 200-350 g were sacrificed and the hearts were rapidly removed and warmed Krebs-Henseleit.
Placed in buffer solution. Separate the left atrium from the heart, and Krebs-Hens
Suspend in 30 mL of jacketed isolated organ bath filled with eleit buffer,
Oxygenated with 5% O ₂ /5% CO ₂ and kept at 37 ° C. The tissue was attached to a force displacement transducer with a resting tension of 1 gram. The atrium was electrically stimulated with a duration of 1 Hz, 1 msec and a super-maximal voltage to cause regular contraction of the tissue.

Adenosine A ₁ agonists were added to the bath in increasing cumulative concentrations until a maximum reduction in contractile force was obtained. Since the adenosine A ₁ agonist has only a small direct negative inotropic effect in the rat atrium, it maximizes the negative inotropic response,
In order to thereby facilitate the measurement, it was necessary to stimulate the β-adrenergic receptor to produce positive muscle inotropic properties. Under these conditions, adenosine A ₁ agonists acting on the A ₁ receptor indirectly reduced β-adrenergic-mediated positive muscle inotropic properties. Therefore, the β-adrenergic agonist isoproterenol (10 ^-8 M) was added to the adenosine A ₁ agonist at about 1
Added to the organ bath 5 minutes ago.

[0048]   The results are shown in the table below:

[0049]

[Table 1] These data demonstrate the high degree of in vitro potency for this series of compounds at the adenosine A ₁ receptor.

Example 2 In Vivo Activity Two days before each experiment, male Sprague-Dawley rats were given pentobarbital sodium 50 mg / kg i.p. p. Anesthesia and surgically implanted indwelling catheters into the carotid artery and jugular vein. Rats were conscious and unrestrained during all subsequent experiments. Attach the carotid cannula to the pressure transducer,
Blood pressure was then recorded continuously throughout each experiment using a Grass polygraph.
Heart rate was derived from blood pressure signals using the Grass tachygraph. The measured parameters were allowed to stabilize for 30 to 90 minutes prior to administration of test compound.

Test compounds were administered either by oral feeding using a curved bulbed oral dosing cannula or intravenously via a jugular indwelling catheter. Orally dosed rats were fasted overnight prior to dosing and had free access to water. Heart rate response after intravenous administration of test compound returned to baseline rapidly so that more than one dose of test compound can be administered to each rat.
However, the response to oral administration of the test compound is a long duration response,
And therefore only one dose could be administered to each rat.

Area under curve of bradycardia (AUC) versus time after intravenous administration and A after oral administration
Comparison with UC was used as a measure of oral bioavailability. The results are shown in the table below:

[0053]

[Table 2] Substantial oral bioavailability is a crucial property in compounds to allow ease of long-term administration. From these data, the 5'-hydroxyethyl substituent interferes with oral bioavailability and
It is clear that the alkyl-substituted derivatives (wherein the alkyl contains 1 to 3 carbons) have good oral activity.

Example 3 Discrimination of Negative Transconducting Activity from Coronary Artery Vasodilation The method of Langendorff, in which the rat isolated heart is perfused in a retrograde fashion at constant pressure through the aorta. Was prepared according to. Blood flow in coronary vessels was determined by measuring the volume of fluid exiting the heart. Heart rate was maintained at 360 beats per minute by electrical pacing of the right atrium. AV room (AV
) Conduction was determined as the time from atrial stimulation to the onset of ventricular depolarization (SV interval).

Compound A causes a concentration-dependent slowing of AV conduction, with a maximum increase in SV interval at an average concentration of 6.8 nM and a maximum increase in AV conduction block of 8.3 n.
At an average concentration of M. At these concentrations, Compound A had no effect on blood flow in the coronary arteries. This demonstrates that Compound A is a potent adenosine A ₁ receptor agonist that induces maximal negative transconductivity at doses that have no effect on coronary vasodilation.

Example 4: Distinction of negative chronotropic activity from hypotensive activity Male Sprague-Dawley rats were treated with sodium pentobarbital 5
0 mg / kg i. p. Anesthesia was performed and the indwelling catheter was surgically implanted into the carotid artery and jugular vein 2 days before each experiment. Rats were conscious and unrestrained during all subsequent experiments. A carotid cannula was attached to the pressure transducer and blood pressure was recorded continuously throughout each experiment using a Grass polygraph. Heart rate was derived from blood pressure signals using a Grass tachygraph. The measured parameters were allowed to stabilize for 30-90 minutes prior to administration of test compound.

Compound A was administered by intravenous administration via a jugular indwelling catheter or by oral gavage using a curved spherical oral dosing cannula. Food and water were available ad libitum.

The ED ₅₀ value at which induction of bradycardia was found was 120 at 0.1 μg / kg / min intravenously.
Minutes, which caused an average of 34% reduction in heart rate, while mean blood pressure remained unchanged. It has been demonstrated that an intravenous dose range of 0.05 μg / kg / min to 0.1 μg / kg / piece does not cause changes in blood pressure. Similarly, 30μ
An oral dose range of g / kg to 100 μg / kg produced no changes in blood pressure and
The g / kg dose caused an average of 40% reduction in heart rate. This demonstrates that a highly significant negative chronotropic effect is evident for the exemplified compounds at doses with no effect on blood pressure.

Example 5 Demonstration of Negative Chronotropic and Negative Chronotropic Activities in Spontaneously Beating Hearts Guinea pig isolated hearts, coronary vasculature and aortic constant pressure were used. Was prepared according to the method of Langendorff perfused in a retrograde manner. Compound A
Were administered to spontaneously beating hearts by infusion into a perfusion line that supplies buffer to the coronary vasculature. The concentration of Compound A was adjusted by changing the infusion rate and / or by changing the concentration of the infusion solution. The concentration of Compound A present in the perfusate was calculated by dividing the rate of infused Compound A by the coronary flow velocity. The spontaneously beating heart rate and AV interval were recorded.

The results of this experiment are shown in FIG. Compound A produced a concentration-dependent slowing of AV conduction, with a maximal increase in AV interval showing a 34% increase over baseline. Compound A also caused a concentration-dependent decrease in heart rate with an EC ₅₀ value of 3.2 nM and a maximum decrease in heart rate of 58%.

Example 6 Demonstration of the Effect of Heart Rate on Negative Transduction Activity Guinea pig isolated hearts were prepared according to the method described in Example 5. In the first part of the experiment, designed to determine the effect of heart rate on the negative transconductivity activity of Compound A, the heart was either spontaneously beaten or 20 per minute.
0 beats (about 20% greater than spontaneous rate) or 300-36 per minute
It was electrically paced with zero beats (about 80% greater than spontaneous rate). Atrioventricular (AV) conduction interval (AV interval) was determined as the time from atrial stimulation to the onset of ventricular depolarization. AV interval measurements were performed at each pacing rate with increasing concentrations of Compound A as described in Example 5. Upon electrical pacing at 200 beats per minute, Compound A at an average concentration of 3.9 nM produced an average increase in AV interval of up to 58% and cardiac block at an average minimum concentration of 5.1 nM. occured. Upon electrical pacing at 300-360 beats per minute, Compound A at an average concentration of 1.45 nM increased on average 20% in the AV interval and at an average minimum concentration of 2.1 nM. Caused a heart block. The results are shown in the table below,
Data from spontaneously beating hearts are included for comparison purposes:

[0062]

[Table 3] These data demonstrate that the negative transconduction effect produced by the exemplified compounds was rate-dependent, with an increase in potency for Compound A shown as pacing rates increased.

Example 7 Demonstration of Negative Metabotropic Activity in an Experimental Model of Paroxysmal Supraventricular Tachycardia Using the experimental conditions described in Example 6, individual hearts were paced at 200 bpm for 1 minute and 300 bpm. The 1 minute pacing at 10 minutes suddenly continued, after which the pacing rate was returned to 200 bpm. The 300 bpm pacing cycle was intended to stimulate an episode of supraventricular tachycardia. This series of pacings was performed in the presence of vehicle and in increasing concentrations of Compound A. The results are shown in Figure 2. 2n which had almost no effect on the AV interval at 200 bpm
Compound A, at an average concentration of M, AVed within 30 seconds during a 300 bpm episode.
Guided the block. When the pacing rate was returned to 200 bpm, the AV interval also returned to near normal values.

Example 8 Distinguishing Negative Chronotropic Activity from Coronary Vasodilation in Pacing Hearts The differential potency of Compound A for negative chronotropic activity on coronary vasodilation in paced hearts was determined. To determine, a different set of experiments was performed in which individual hearts were used to collect the measurements for each effect. Using experimental conditions as described in Example 6, isolated hearts of guinea pigs were 300-3 per minute.
Pacing with 60 beats. AV conduction intervals were determined as described in Example 6. Coronary perfusate flow data was determined by measuring the volume of solution exiting the heart. AV conduction interval data and coronary perfusate flow data were collected in the presence of increasing concentrations of Compound A. Results are shown in Figure 3, with dose-related increases in both AV conduction interval and coronary perfusate flow. The distinction for these effects is readily apparent. Compound A producing the greatest increase in AV conduction time
The average concentration was 0.76 nM. The concentration of Compound A (EC ₅₀ ) that produced half-maximal effect on coronary perfusate flow was 32 nM. Compound A was 40-fold more potent at slowing AV conduction time than it was at increasing coronary perfusate flow.

Although the present invention has been fully described herein, the present invention is within a broad and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiments thereof. It will be appreciated by those skilled in the art that the invention may be practiced. All patents, patent applications and publications cited herein are fully incorporated by reference herein in their entireties.

[Brief description of drawings]

[Figure 1]   Figure 1 shows ethyl N in isolated spontaneously beating hearts of guinea pigs. ⁶ -Cyclopentyladenosine-5'-uronamide (Compound A) negative chronotropic
HR = heart rate, bpm = beats per minute
, Msec = millisecond. Compound A produced a concentration-dependent slowing of AV conduction,
The maximum increase in distance represents a 34% increase over baseline. Compound A is also a heart
An EC of 3.2 nM with a concentration-dependent decrease in heart rate₅₀Value and 58%
It has a maximum reduction in heart rate.

FIG. 2 shows negative transconductivity effects of Compound A in a guinea pig isolated heart model of paroxysmal supraventricular tachycardia (PSVT); HR = heart rate, bpm = beats per minute,
msec = millisecond. An average concentration of 2 nM of Compound A, which had little effect on the AV interval at 200 bpm pacing, induced AV block within 30 seconds during a 300 bpm pacing episode. Pacing is 200bp
When returning to m, the AV interval also returned to near normal values. Therefore PSVT
The effect of Compound A in this experimental model of A was rate-dependent, such that Compound A causes a greater increase in AV conduction interval at higher pacing rates.

FIG. 3. Compound A in isolated electrically paced hearts of guinea pigs.
, Negative coronary conductance and coronary vasodilation; CPF = coronary perfusate flow, mL = milliliter. Under pacing conditions of 300-360 beats per minute, an average concentration of 0.76 nM Compound A averages up to 2 AV intervals.
A 3% increase and an average concentration of 1.09 nM resulted in heart block. Under these same pacing conditions, Compound A was found to have an average flow rate of 8.5 mL / min of 14.2.
There was a concentration-dependent increase in coronary perfusate flow to a mean flow rate of mL / min. Mean concentration of Compound A (EC ₅₀ ) resulting in 50% of maximum increase in coronary perfusate flow
Was 32 nM. Therefore, Compound A was more than 40-fold more potent in slowing AV conduction than in increasing coronary perfusate flow.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE, TR), OA (BF , BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ , UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, B Z, CA, CH, CN, CR, CU, CZ, DE, DK , DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, J P, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, R O, RU, SD, SE, SG, SI, SK, SL, TJ , TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW

Claims (44)

[Claims] 1. A compound of the following formula: embedded image Or the use of a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for treating a cardiac rhythm disorder in a mammal that would benefit from the induction of a negative chronotropic effect, a negative chronotropic effect or a combination thereof. The use, wherein R ₁ is C _3-7 secondary alkyl, or C _3-8 cycloalkyl; and R ₂ is C _1-4 alkyl or C _3-5 cycloalkyl. 2. The use according to claim 1 wherein R ₁ is 3-pentyl, cyclopentyl or norbornyl; and R ₂ is methyl, ethyl, isopropyl or cyclopropyl. 3. The use according to claim 1, wherein the drug is in a parenteral dosage form. 4. The use according to claim 3, wherein the drug is in an intravenous dosage form. 5. The use according to claim 1, wherein the drug is an oral dosage form. 6. Use according to claim 1, wherein R ₂ is ethyl. 7. Use according to claim 1, wherein R ₂ is cyclopropyl. 8. The use according to claim 1, wherein R ₁ is 3-pentyl. 9. Use according to claim 1, wherein R ₁ is cyclopentyl. 10. Use according to claim 9, wherein R ₂ is ethyl. 11. Use according to claim 9, wherein R ₂ is cyclopropyl. 12. The compound is N ⁶ -cyclopentyl-5 ′-(N-ethyl) carboxamide adenosine, N ⁶ -cyclopentyl-5 ′-(N-cyclopropyl) carboxamide adenosine, N ^6- (3-pentyl). -5 '- (N-ethyl) carboxamide adenosine, N ⁶ - cyclopentyl -5' - (N-methyl) carboxamide adenosine, and N ⁶ - cyclopentyl -5 '- (N-t-
Use according to claim 4, selected from the group consisting of butyl) carboxamide adenosine, and pharmaceutically acceptable salts and esters thereof. 13. The use according to claim 4, wherein the compound is N ^6- (3-pentyl) -5 ′-(N-ethyl) carboxamidoadenosine. 14. The use according to claim 3, wherein the compound is N ⁶ -cyclopentyl-5 ′-(N-ethyl) carboxamidoadenosine. 15. The use according to claim 3, wherein the compound is N ⁶ -cyclopentyl-5 ′-(N-cyclopropyl) carboxamidoadenosine. 16. The use according to claim 5, wherein the compound is N ⁶ -cyclopentyl-5 ′-(N-ethyl) carboxamidoadenosine. 17. The use according to claim 5, wherein the compound is N ⁶ -cyclopentyl-5 ′-(N-cyclopropyl) carboxamidoadenosine. 18. The cardiac rhythm disorder is supraventricular tachyarrhythmia.
Use as described in. 19. The use according to claim 1, wherein the cardiac rhythm disorder is paroxysmal supraventricular tachycardia. 20. The use according to claim 1, wherein the cardiac rhythm disorder is atrial fibrillation. 21. A method for the treatment of cardiac rhythm disorders in a mammal that would benefit from the induction of negative dromotropic and / or negative chronotropic effects, comprising:
The method comprises an effective amount of a compound of the formula: Or administering a pharmaceutically acceptable salt or ester thereof to the mammal; wherein R ₁ is C _3-7 secondary alkyl, or C _3-8 cycloalkyl; The method wherein R ₂ is C _1-4 alkyl or C _3-5 cycloalkyl. 22. The method of claim 21, wherein R ₁ is 3-pentyl, cyclopentyl or norbornyl; and R ₂ is methyl, ethyl, isopropyl or cyclopropyl. 23. The compound of claim 2, wherein the compound is administered in a parenteral dosage form.
The method according to 1. 24. The method of claim 23, wherein the compound is injected intravenously. 25. The compound of claim 21, wherein the compound is administered in an oral dosage form.
The method described in. 26. The method of claim 21, wherein R ₂ is ethyl. 27. The method of claim 21, wherein R ₂ is cyclopropyl. 28. The method of claim 21, wherein R ₁ is 3-pentyl. 29. The method of claim 21, wherein R ₁ is cyclopentyl. 30. The method of claim 29, wherein R ₂ is ethyl. 31. The method of claim 29, wherein R ₂ is cyclopropyl. 32. The compound is N ⁶ -cyclopentyl-5 ′-(N-ethyl) carboxamide adenosine, N ⁶ -cyclopentyl-5 ′-(N-cyclopropyl) carboxamide adenosine, N ^6- (3-pentyl). -5 '- (N-ethyl) carboxamide adenosine, N ⁶ - cyclopentyl -5' - (N-methyl) carboxamide adenosine, and N ⁶ - cyclopentyl -5 '- (N-t-
25. The method of claim 24, wherein the method is selected from the group consisting of butyl) carboxamide adenosine, and pharmaceutically acceptable salts and esters thereof. 33. The method of claim 24, wherein the compound is N ^6- (3-pentyl) -5 ′-(N-ethyl) carboxamidoadenosine. 34. The method of claim 23, wherein the compound is N ⁶ -cyclopentyl-5 ′-(N-ethyl) carboxamide adenosine. 35. The method of claim 23, wherein the compound is N ⁶ -cyclopentyl-5 ′-(N-cyclopropyl) carboxamidoadenosine. 36. The method of claim 25, wherein the compound is N ⁶ -cyclopentyl-5 ′-(N-ethyl) carboxamidoadenosine. 37. The method of claim 25, wherein the compound is N ⁶ -cyclopentyl-5 ′-(N-cyclopropyl) carboxamidoadenosine. 38. The cardiac rhythm disorder is supraventricular tachyarrhythmia.
The method according to 1. 39. The cardiac rhythm disorder is paroxysmal supraventricular tachycardia.
The method described in. 40. The method of claim 21, wherein the cardiac rhythm disorder is atrial fibrillation. 41. A pharmaceutical composition in unit dosage form, which comprises both one or more active ingredients and one or more pharmaceutically acceptable excipients, wherein the improvement is that one or more unit doses are administered. In a mammal to treat or prevent a cardiac rhythm disorder, a compound of the following formula: Or a pharmaceutically acceptable salt or ester thereof; wherein R ₁ is C _3-7 secondary alkyl, or C _3-8 cycloalkyl; and R ₂ is C _1-4 alkyl or A pharmaceutical composition which is _C3-5 cycloalkyl. 42. The pharmaceutical composition of claim 41, wherein the cardiac rhythm disorder is a cardiac rhythm disorder that benefits from the induction of negative dromotropic effects, negative chronotropic effects or a combination of such effects. . 43. An orally administrable form, and said amount is from about 1 to about 5.
42. The pharmaceutical composition according to claim 41, which is 0 μg / kg body weight. 44. Intravenous injectable form, and said amount is about 0.1.
42. The pharmaceutical composition of claim 41, which is about 10 [mu] g / kg / min.