HK1093018A - Use of 3,7-diazabicyclo[3,3,1] nonane compounds for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients - Google Patents

Description

Use of 3, 7-diazabicyclo [3, 3, 1] nonane compounds for the treatment and/or prophylaxis of cardiac arrhythmias in male patients

The present invention relates to a novel medical use of 3, 7-diazabicyclo- [3, 3, 1] nonane compounds, preferably 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] -nonane compounds, and most preferably tedisamil, and pharmaceutically acceptable acid addition salts and/or solvates of said compounds.

The 9, 9-alkylene-3, 7-diazabicyclononane compounds of formula I and their pharmaceutical activity are known from published European patent EP 103,833 and the corresponding U.S. Pat. No.4,550,112, and Finnish patent FI 76,338. The compounds of formula I are a subgroup of the 9, 9-N, N' -tetrasubstituted 3, 7-diaza-bicyclo [3, 3, 1] nonane compounds described in the above patent specification and which can be prepared by the methods described therein. The above patent specification discloses that such compounds have useful cardiac activity, in particular conventional oxygen storage and action on heart rate and rhythm, and very high physiological tolerability. Thus, this compound exhibits satisfactory antiarrhythmic activity even at low doses. Moreover, the undesirable negative effects on cardiac contractility are extremely low; i.e. the ratio of the refractory period of the antiarrhythmic or prolonged cardiac activity of this compound to the secondary activity of negative muscle strength is particularly good.

Also, Burow et al are described in U.S. patent No.5,164,401: the compound also has remarkable diuretic effect, and has good ratio of excretion of sodium to potassium.

Furthermore, specific salts of 3, 7-diazabicyclo [3, 3, 1] -nonane compounds, in particular 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] nonane compounds, and processes for their preparation are described in US 5,324,732. Thus, the fumarate salt of the compound is described in US 5,324,732, wherein 1.5 moles of fumaric acid are present per mole of this compound. This document also provides reference to some of the conventional pharmacological activities of the compounds of formula I described in published european patent EP 103,833 and corresponding us patent No.4,550,112. U.S. patent No.4,912,113 also provides novel 3, 7-diazabicyclo [3, 3, 1] nonane compounds and their pharmacological properties, as well as intermediates. However, none of the cited patents suggest any difference in the effect of using tedisamil with patients of different sexes.

It is worth mentioning that the patent literature of the prior art referred to does not include any clinical data on humans, however, all pharmacological evidence provided is limited by preclinical testing of animals such as rats and dogs. In addition, the results of some preclinical experiments are also described in the scientific literature. As described by Fischbach et al, "Tedisamide in a viral mine Model of atomic Flutter" (Journal of Cardiovascular Pharmacology, vol.34, No.2, 1999, 8 months, pages 212 to 218), and "Conversion of atomic fibre by the Experimental analytical therapy in Two mine Models" (Journal of Cardiovascular Electropathology, vol.12, No.10, 2001, 10 months, 1138 to 1144). However, Fischbach et al did not suggest any difference in effect when tedisamil was administered to patients of different sexes. Opie et al discuss "Tedisamide in CoronoryDisase: additional Benefits in Therapy of atomic fibrosis? "(Journal of Cardiovascular pharmacy and Therapeutics, vol.8, No. supplement 1, 2003, p.S. 33 to S37). They presented data and graphs investigating the effect of isolated coronary artery ligated rat hearts, and tedisamil, on exercise-induced ischemia in diastole and systole, and myocardial oxygen depletion in exercise dogs. Tedisamil is also stated to have anti-ischemic effects in heart studies in rats, rabbits, running dogs and humans; however, Opie et al did not suggest any difference in effect when tedisamil was administered to patients of different sexes.

Furthermore, "Effects of Bertosamine on Attribute and Ventrical Treshold for Fibrillo-Flutter in company with Quinidine in Anaesthexized Cats" (pharmaceutical Research, vol.25, No. supplement 2, 1992, pages 156 to 157), and "Effects of Bertosamine on Rabbit Attribute and Ventrical Transmembrane Potentials" (pharmaceutical Research, vol.25, No. supplement 2, 1992, pages 139 to 140) have been described by Julius Papp et al. However, Papp et al also did not suggest any difference in effect when tedisamil was administered to patients of different sexes.

Although the research topic of Nicholas a. flores on the clinical stage of humans is "tesiamil Solvay" in Current Opinion in Investigational Drugs, vol.2, No.1, 2001, pages 97 to 103), no difference in the effect of Tedisamil on patients of different sexes was reported.

The object of the present invention is to provide a new medical use or a new method for treating a male patient in need of treatment and/or prevention of an antiarrhythmic.

It is another object of the invention to provide novel antiarrhythmic pharmaceutical compositions with improved activity profile for male patients.

The object of the present invention is achieved by the surprising discovery that 3, 7-diazabicyclo- [3, 3, 1] nonane compounds, preferably 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] -nonane compounds, and most preferably tedisamil, and pharmaceutically acceptable acid addition salts and/or solvates of said compounds are particularly suitable for the treatment and/or prophylaxis of anti-arrhythmic events in male patients, preferably the conversion of recent episodes of atrial fibrillation (Afib) or flutter to Normal Sinus Rhythm (NSR) in male patients. According to a further aspect of the invention, the object is achieved by providing an antiarrhythmic pharmaceutical composition comprising an antiarrhythmic effective amount of at least one 3, 7-diaza-bicyclo [3, 3, 1] nonane compound having antiarrhythmic activity in a male patient as described herein.

The subject of the present invention is therefore the use of 3, 7-diaza-bicyclo [3, 3, 1] nonane compounds, their physiologically acceptable acid addition salts and/or their solvates for the preparation of a medicament for the treatment and/or prophylaxis of an antiarrhythmic in a male patient, preferably for converting a recent onset of atrial fibrillation (Afib) or flutter to a normal sinus heart rate (NSR) in a male patient.

The compounds suitable for this new medical use in male patients are 3, 7-diazabicyclo [3, 3, 1] nonane compounds according to formula I:

wherein

R1 represents an alkyl group having 1 to 6 carbon atoms, an alkylene group having 3 to 6 carbon atoms and having one double bond not directly bonded to the nitrogen atom, a cycloalkylalkyl group having 4 to 9 carbon atoms or a benzyl group,

r2 represents lower alkyl, and

r3 represents lower alkyl, or

R2 and R3 together form an alkylene chain containing 3 to 6 carbon atoms, and

r4 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 to 6 carbon atoms which has a double bond not directly linked to the nitrogen atom, a cycloalkylalkyl group having 4 to 9 carbon atoms, a group corresponding to formula a:

wherein

R5 represents hydrogen, halogen, lower alkyl or lower alkoxy, and

z represents an alkylene chain containing 1 to 3 carbon atoms or a propyleneoyl chain having one double bond conjugated to a phenyl group, or a group corresponding to formula b:

wherein

R6 represents hydrogen, halogen, lower alkyl or lower alkoxy, and

r7 represents hydrogen, halogen, lower alkyl or lower alkoxy.

The compounds according to the invention which are particularly suitable for the novel medical use in male patients are compounds of the formula I in which R1 represents alkyl having 1 to 6 carbon atoms or cycloalkylalkyl having 4 to 7 carbon atoms. In other preferred compounds of the formula I, the substituent R4 represents alkyl having 1 to 6 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, or a radical corresponding to formula b.

Preferred compounds for the novel pharmaceutical use according to the invention in male patients are compounds of formula I, wherein R1 represents alkyl having 3 to 6 carbon atoms or cycloalkylalkyl having 4 to 7 carbon atoms, and R4 represents alkyl having 3 to 6 carbon atoms or cycloalkylalkyl having 4 to 7 carbon atoms, and the physiologically acceptable acid addition salts and/or solvates thereof. The 3, 7-diazabicyclo- [3, 3, 1] nonane compound may be a 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] nonane compound of formula I, wherein R2 and R3 together form an alkylene chain containing from 4 to 5 carbon atoms, and R1 and R4 independently of one another represent a linear or branched alkyl group having from 3 to 4 carbon atoms or a cyclopropylmethyl group.

A preferred salt of this group of compounds is the fumarate salt of a 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] nonane compound, in which 1.5 mol of fumaric acid are present per mol of compound of formula I.

Other preferred compounds for the novel pharmaceutical use according to the invention for male patients are selected from N, N '-dicyclopropyl-methyl-9, 9-tetramethylene-3, 7-diazabicyclo [3, 3, 1] nonane (tedisamil), N-isobutyl-N' -isopropyl-9, 9-pentamethylene-3, 7-diazabicyclo [3, 3, 1] nonane, and the physiologically acceptable acid addition salts and/or solvates thereof. Preferred salts of this group of compounds are the fumarate salts of N, N '-dicyclopropylmethyl-9, 9-tetramethylene-3, 7-diazabicyclo [3, 3, 1] nonane (tedisamil) or N-isobutyl-N' -isopropyl-9, 9-pentamethylene-3, 7-diazabicyclo [3, 3, 1] nonane, wherein 1.5 moles of fumaric acid are present per mole of the 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] -nonane compound.

Alternatively, the hydrochloride, which is an acid addition salt of a 3, 7-diazabicyclo [3, 3, 1] nonane compound, is also well suited for the novel medical use according to the invention in male patients.

Particularly preferred 3, 7-diazabicyclo [3, 3, 1] nonane compounds are the 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] nonane compounds tedisamil and physiologically suitable acid addition salts and/or solvates thereof, which are the most preferred compounds for the preparation of pharmaceutical preparations for the treatment and/or prophylaxis of anti-arrhythmic events in male patients, preferably for converting recent episodes of atrial fibrillation (Afib) or flutter to normal sinus heart rate (NSR) in male patients. If an acid addition salt of tedisamil is used, it may be used according to the invention preferably in the form of tedisamil hydrochloride or in the form of tedisamil sesquifumarate for the treatment of male patients. Other pharmacologically suitable acid addition salts of tedisamil are known from european patent EP 103,833. Thus, salts of inorganic acids such as sulfuric acid or hydrohalic acids, especially hydrochloric acid; or salts of organic acids, such as lower aliphatic monocarboxylic or dicarboxylic acids, such as acetic acid, fumaric acid, tartaric acid, lactic acid, maleic acid, citric acid or salicylic acid; or salts of sulfonic acids, such as lower alkylsulfonic acids, for example methanesulfonic acid, or benzenesulfonic acids optionally substituted on the phenyl ring by halogen or lower alkyl, for example p-toluenesulfonic acid, are suitable as physiologically acceptable acid addition salts of the compounds of the formula I.

Surprisingly, in addition to the above-mentioned known conventional cardioactive properties, it has been found that 3, 7, 9, 9-tetrasubstituted 3, 7-diazabicyclo [3, 3, 1] nonane compounds conforming to formula I have a good effect in the anti-arrhythmic activity in male patients, in particular in the conversion of the recent onset of atrial fibrillation (Afib) or flutter to Normal Sinus Rhythm (NSR) in male patients. The better antiarrhythmic effect of the compounds of formula I on male patients, in particular the conversion of the recent onset of atrial fibrillation (Afib) or flutter in male patients to normal sinus heart rate (NSR), can be demonstrated by clinical test data of the patients, which demonstrates that 3, 7-diazabicyclo [3, 3, 1] nonane compounds, such as tedisamil and acid addition salts thereof, are surprisingly suitable for the treatment and/or prophylaxis of antiarrhythmias in male patients, preferably the conversion of the recent onset of atrial fibrillation (Afib) or flutter in male patients to normal sinus heart rate (NSR).

Description of clinical study design and results

A) Phase II clinical study of patients

Analysis of the initial study in humans has surprisingly shown that the efficacy is sexually different, as male patients have higher rates of conversion compared to females when treated with tedisamil. In addition, male patients present fewer safety issues than female patients. Thus, it was surprisingly found that tedisamil is specific for male patients in anti-arrhythmic therapy, and in particular in converting the recent onset of atrial fibrillation (Afib) to normal sinus heart rate (NSR), compared to female patients.

This initial clinical study in humans was a multicenter, double-blind, randomized, placebo-controlled, sequentially ascending dose group study to assess the efficacy and safety of intravenously administered tedisamil to rapidly transition to normal sinus heart rate in patients with atrial fibrillation or flutter. The active ingredient used was tedisamil dihydrochloride. The study was designed in a phase II study and was conducted in 35 to 40 centers in 3 to 4 countries. The research period is as follows: screening: up to 48 hours; treatment (in patients): infusion alone for 30 minutes; and (4) security tracking: continuous telemetry (telemetric) for 24 hours (in the patient) and 28 days of safety tracking.

The primary efficacy study was conducted to determine the percentage of patients who transitioned to normal sinus heart rate (NSR) (at least 60 seconds) at any time within 2.5 hours after initiation of human infusion to demonstrate that any dose of tedisamil is superior to placebo in terminating atrial fibrillation/flutter. The purpose of the secondary effect was to determine the percentage of patients who maintained sinus heart rate 2.5 hours after the start of intravenous infusion compared to placebo; determining the percentage of patients who maintained sinus heart rate 24 hours after the start of intravenous infusion compared to placebo; determining the transition time of tedisamil compared to placebo after the start of infusion; and determining a dose-and plasma concentration-response relationship for tedisamil compared to placebo. The purpose of safety is as follows: the safety and tolerability of tedisamil compared to placebo was determined.

The following methodologies were applied for the investigators: a multicenter, double-blind, randomized, placebo-controlled, sequentially ascending dose group study to evaluate the efficacy and safety of intravenously-administered tedisamil compared to placebo. The study drug was infused for more than 30 minutes, reaching half the dose in 10 minutes and the other half in the remaining 20 minutes. The first group of patients received 0.4mg/kg body weight (bw), and were infused at 0.2mg/kg bw over 10 minutes, and continued infusion at 0.2mg/kg bw over 20 minutes. Only after the initial dose has been evaluated (double-blind) and found to be safe, the next higher dose of 0.6mg/kg bw is given (0.3 mg/kg bw infused over 10 minutes, 0.3mg/kg bw continued to be infused over 20 minutes). A higher dose may be added in the third stage. Plasma drug concentrations of tedisamil were assessed at 24 hours and at relapse after infusion (at 10 and 30 minutes) at the transition to normal sinus heart rate, after infusion began.

Number of planned subjects: randomly selected 330 (110 patients per dose group)

Major criteria for diagnosis and conclusion：

Atrial fibrillation or flutter within > 3 hours and < 48 hours was taken as the first or recurrent episode.

Test products, dosing and modes of administration：

Tedisamil (0.4mg/kg body weight)

Tedisamil (0.6mg/kg body weight)

Are all doses administered intravenously.

Reference treatments, dosing and modes of administration：

Placebo (vehicle) was administered by intravenous infusion for 30 minutes.

Treatment cycle：

The total infusion time was 30 minutes with half of the dose infused over 10 minutes and the other half infused over the remaining 20 minutes.

Evaluation criteria：

1) Therapeutic effect：

Primary curative effect: percentage of patients who transitioned to normal sinus heart rate (at least 60 seconds) at any time within 2.5 hours after the start of infusion of the study drug.

Secondary curative effect: percentage of patients with NSR 2.5 and 24 hours after infusion initiation; the time of the transition; dose-and concentration-response relationships.

2) Safety feature：

Physical examination, ECG, 24-hour accommodation monitoring, vital signs, laboratory assessments, and adverse reactions.

The statistical method comprises the following steps:

all efficacy variables were evaluated for patients with atrial fibrillation and patients with atrial flutter, respectively. The percentage of conversion in the treatment groups was compared using a factorized logistic regression model for the treatment groups and the center. The transition times in the treatment groups were compared using Cox presentation halders models with factors for the treatment groups and the center. Dose-response and concentration-response relationships were determined using descriptive statistics.

For the calculation of patient figures, the following assumptions are made:

1. for patients with atrial fibrillation, the percentage of transition to normal sinus heart rate in the placebo group (at any time within 2.5 hours after infusion began) was 20% and the clinically relevant difference was 20%.

2. For atrial flutter patients, the percentage of normal sinus heart rate conversion in the placebo group was 10% and the clinically relevant difference was 40%.

Interim analysis of efficacy was performed with external statistics midway between the first and second stages. The aim is to end the phase when the dose of tedisamil used is ineffective in that phase. Technically, each interim analysis is a calculation of the prediction power for comparing the primary efficacy variables of tedisamil and placebo. In addition, double-blind safety studies and efficacy analyses were performed simultaneously at the end of each phase (if applicable).

B) Human phase III clinical study

Analysis of the second study in humans confirmed findings from the first study, such as gender differences with respect to efficacy, such as higher rates of transformation in male patients than female patients when treated with tedisamil.

This human secondary clinical Study was a multicenter, double-blind, randomized, placebo-controlled, Parallel Design Study (Parallel Design Study) to evaluate the efficacy and safety of intravenously administered tedisamil sesquifumarate for the rapid shift to normal sinus heart rate in subjects with recent episodes of atrial fibrillation or flutter.

The active ingredient used was tedisamil sesquifumarate. The study was designed at the time of the phase II study and was conducted in 30 to 40 centers in 5 countries. The research period is as follows: screening: up to 48 hours; treatment: single infusion (in patient) for 30 minutes; and (4) security tracking: telemetry (in the patient) was continued for 24 hours and safety tracking for 28 days.

The objective of primary efficacy in the study was to measure the percentage of subjects who transitioned within any time period of 2.5 hours after infusion began demonstrating that any dose of tedisamil sesquifumarate outperforms placebo in rapidly transitioning to normal sinus heart rate (at least 60 seconds). The purpose of the secondary effect was to determine the percentage of subjects who transitioned to normal sinus heart rate at any time within 2.5 hours after the start of intravenous infusion and normal sinus heart rate at 2.5 hours after the start of infusion compared to placebo; determining the percentage of subjects who transitioned to normal sinus heart rate at any time within 2.5 hours after the start of intravenous infusion and normal sinus heart rate 24 hours after the start of infusion when tedisamil sesquifumarate was compared to placebo; determining the percentage of subjects who transitioned to normal sinus heart rate and discharged normal sinus heart rate at any time within 2.5 hours after the start of intravenous infusion; determining the time at which tedisamil sesquifumarate transitioned to normal sinus heart rate after infusion began as compared to placebo; determining a dose-and concentration-response relationship for tedisamil sesquifumarate compared to placebo; and determining the energy required for DC cardioversion of tedisamil sesquifumarate as compared to placebo. The purpose of safety is as follows: the safety and tolerability of tedisamil sesquifumarate was determined compared to placebo.

The following methodology was applied: a multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of intravenously-administered tedisamil sesquifumarate compared to placebo. The study drug was infused over 30 minutes, reaching half the dose in 10 minutes and the other half in the remaining 20 minutes.

Subjects were randomly assigned to receive:

-0.32 mg tedisamil free base per kg body weight (bw) (0.16 mg/kg bw in 10 minutes, followed by 0.16mg/kg bw in 20 minutes); or

-0.48 mg tedisamil free base per kg bw (0.24 mg/kgbw in 10 minutes, followed by 0.24mg/kg bw in 20 minutes); or

-0.64 mg tedisamil free base per kg bw (0.32 mg/kgbw in 10 minutes, followed by 0.32mg/kg bw in 20 minutes); or

Infusion of placebo for 30 minutes.

Number of planned subjects:

212 randomly selected subjects with atrial fibrillation (53 subjects per treatment group).

These subjects are the primary target population. In addition, 80 subjects (20 per treatment group) who were considered to have atrial flutter were recorded within the scope of this study.

However, if the number of planned atrial fibrillation subjects is reached, the study may be ended even though not all subjects with atrial flutter have been recorded.

Main criteria for diagnosis and conclusion:

atrial fibrillation or flutter was the first or recurrent episode in > 3 hours and < 45 days.

Test product, dose and mode of administration:

tedisamil free base 0.32mg/kg body weight (equivalent to 0.51mg/kg tedisamil sesquifumarate and 0.4mg/kg tedisamil dihydrochloride

Tedisamil free base 0.48mg/kg body weight (equivalent to 0.77mg/kg tedisamil sesquifumarate and 0.6mg/kg tedisamil dihydrochloride

Tedisamil free base 0.64mg/kg body weight (equivalent to 1.02mg/kg tedisamil sesquifumarate and 0.8mg/kg tedisamil dihydrochloride

The amount is administered intravenously.

The dose of tedisamil in the experimental design refers to the tedisamil free base.

Reference treatment, dosing and mode of administration:

placebo (vehicle) was administered for 30 minutes like tedisamil intravenous infusion.

The treatment period is as follows:

the total infusion time was 30 minutes, half of the dose was infused over 10 minutes and the other half over the remaining 20 minutes.

Evaluation criteria:

1) the curative effect is as follows:

primary curative effect: percentage of subjects who transitioned to normal sinus heart rate (at least 60 seconds) at any time within 2.5 hours after the start of the drug infusion being studied.

The middle-grade curative effect is as follows: percentage of subjects who transitioned to normal sinus heart rate and discharged at any time and 24 hours after infusion began within 2.5 hours, transition time, dose-and concentration-response relationship and DC cardioversion energy.

2) Safety:

physical examination, ECG, 24-hour accommodation monitoring, vital signs, laboratory assessments, and adverse reactions.

The statistical method comprises the following steps:

the percent of conversion in the treatment groups was compared using (Pearson) variance statistics. Time of transition in treatment groups was compared using a time series test. Dose-response and concentration-response relationships and the energy required for DC conversion were examined using descriptive statistics.

Subjects with atrial fibrillation and atrial flutter were analyzed separately. In addition, the two populations are analyzed in groups. The monitoring was performed as an analysis of a population of subjects who were all atrial flutter.

Table I: recent onset of atrial fibrillation (Afib) to NSR

The NSR is switched at any time within 2.5 hours after the infusion begins.

An ITT patient sample; patients with DC cardioversion were excluded.

	Sex (human)	Antiarrhythmic therapy
					Tidesazam		Placebo
		0.4mg/kg	0.6mg/kg
				Atrial fibrillation	Male sex	18/35(51.4％)		18/26(69.2％)	2/24(8.3％)
	Female with a view to preventing the formation of wrinkles	6/17(35.3％)	6/16(37.5％)				2/22(9.1％)
				Atrial flutter	Male sex	1/7(14.3％)		1/5(20.0％)	0/10
	Female with a view to preventing the formation of wrinkles	0/2	2/6(33.3％)				0/3
				All are	Male sex	19/42(45.2％)		19/31(61.3％)	2/34(5.9％)
	Female with a view to preventing the formation of wrinkles	6/19(31.6％)	8/22(36.4％)				2/25(8.0％)

Table II: recent onset of atrial fibrillation (Afib) translates to NSR

The NSR is switched at any time within 2.5 hours after the infusion begins.

Patients with atrial fibrillation

An ITT patient sample; patients with DC cardioversion were excluded.

Sex (human)	Age (age)	Antiarrhythmic therapy
					Tidesazam		Placebo
		0.4mg/kg	0.6mg/kg
				Male sex	< 65 years old	10/20(50.0％)		13/18(72.2％)	1/14(7.1％)
	65 years old ═ 65 years old	8/15(51.4％)	5/8(62.5％)				1/10(10％)
					Total of	18/35(51.4％)		18/26(69.2％)	2/24(8.3％)
Female with a view to preventing the formation of wrinkles	< 65 years old	2/5(40.0％)	1/3(33.3％)				1/5(20.0％)
					65 years old ═ 65 years old	4/12(33.3％)		5/13(38.5％)	1/17(5.9％)
	Total of	6/17(35.3％)	6/16(37.5％)				2/22(9.1％)

Table III: recent onset of atrial fibrillation (Afib) translates to NSR

The NSR is switched at any time within 2.5 hours after the infusion begins.

An ITT patient sample; patients with DC cardioversion were excluded.

	Sex (human)	Antiarrhythmic therapy
					Tidesazam		Placebo
		0.4mg/kg	0.6mg/kg
				Atrial fibrillation	Male sex	18/35(51.4％)		18/26(69.2％)	2/24(8.3％)
	p-value, ChiSq (control placebo)	＜0.001	＜0.001
					Female with a view to preventing the formation of wrinkles	6/17(35.3％)		6/16(37.5％)	2/22(9.1％)
	p-value, ChiSq (control placebo)	＜0.045	＜0.034
				Atrial flutter	Male sex	1/7(14.3％)		1/5(20.0％)	0/10
	p-value, ChiSq (control placebo)	0.218	0.143
					Female with a view to preventing the formation of wrinkles	0/2		2/6(33.3％)	0/3
	p-value, ChiSq (control placebo)	-	0.257
				All are	Male sex	19/42(45.2％)		19/31(61.3％)	2/34(5.9％)
	p-value, ChiSq (control placebo)	＜0.001	＜0.001
					Female with a view to preventing the formation of wrinkles	6/19(31.6％)		8/22(36.4％)	2/25(8.0％)
	p-value, ChiSq (control placebo)	＜0.045	＜0.018

From these data it can be seen that anti-arrhythmic male patients responded more specifically to treatment with tedisamil than anti-arrhythmic female patients, and especially in the transition from the recent onset of atrial fibrillation (Afib) to normal sinus heart rate (NSR).

It is particularly surprising that, as demonstrated by the above-mentioned findings in humans, in the treatment and/or prevention of anti-arrhythmic events in male patients, especially in converting the recent onset of atrial fibrillation (Afib) in male patients to NSR, 3, 7-diazabicyclo- [3, 3, 1] nonane compounds, preferably 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] -nonane compounds, and most preferably tedisamil, and pharmaceutically acceptable acid addition salts and/or solvates thereof, since no difference in therapeutic effect was observed in this human sex before extensive studies using tedisamil for both sexes, in particular in the description of the prior art, no specificity of this sex was observed in preclinical animal studies.

The therapeutic efficacy of tedisamil in patient studies can be concluded from the results that tedisamil, like 3, 7-diazabicyclo- [3, 3, 1] nonane compounds, preferably 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] -nonane compounds, and most preferably tedisamil itself, and acid addition salts thereof, shows higher turnover rates in male patients than in female patients. The extended infusion over time described above does not produce higher transition rates. From the results, the safety can be concluded: almost all people with tdp (torsade de point) (torsade de tachycardia) observed within 30min of dosing are female patients. Only one male patient with high dose showed TdP in 0.72 of the 3114 study.

According to the present invention, 3, 7-diazabicyclo- [3, 3, 1] nonane compounds, preferably 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] -nonane compounds, and most preferably tedisamil, and pharmaceutically acceptable acid addition salts and/or solvates, and conventional pharmaceutical auxiliaries and/or carriers, may be included as therapeutic agents in solid or liquid pharmaceutical formulations for administration to humans. Examples of solid preparations which can be administered orally are tablets, coated tablets, capsules, powders or granules, or alternatively suppositories. These preparations may comprise conventional pharmaceutically acceptable inorganic and/or organic carriers, such as talc, lactose or starch, and conventional pharmaceutical adjuvants, such as lubricants or disintegrating agents for tablets. Liquid formulations, such as suspensions or emulsions of 3, 7-diazabicyclo- [3, 3, 1] nonane compounds, preferably 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] -nonane compounds, and most preferably tedisamil, and pharmaceutically acceptable acid addition salts and/or solvates thereof, may include conventional diluents, such as water, oils and/or suspending agents, such as polyethylene glycol and the like. Other adjuvants such as antiseptic, flavoring agent, etc. can be added additionally.

3, 7-diazabicyclo- [3, 3, 1] nonane compounds, preferably 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] -nonane compounds, and most preferably tedisamil, and pharmaceutically acceptable acid addition salts and/or solvates thereof, may be mixed and prepared in a known manner with pharmaceutical auxiliaries and/or carriers. The 3, 7-diazabicyclo- [3, 3, 1] nonane compound, preferably the 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] -nonane compound, and most preferably tedisamil, and the pharmaceutically acceptable acid addition salts and/or solvates thereof, for use in the preparation of solid pharmaceutical forms for administration to humans, may be mixed in conventional manner with auxiliaries and/or carriers and may be granulated by wet or dry methods. The granules or powder can be directly encapsulated or compressed into tablet cores by conventional methods. These preparations may be coated by known methods, if necessary.

Examples

The pharmaceutical preparations according to the invention containing the active substances of the formula I and the preparation of such pharmaceutical preparations are described in the following examples 1 to 3. The following examples illustrate the preparation of pharmaceutical formulations containing tedisamil dihydrochloride. Pharmaceutical formulations containing tedisamil sesquifumarate are obtained in a similar manner.

Example 1:tablet composition:

20 parts of N, N' -dicyclopropylmethyl-9, 9-tetramethylene-3, 7-diazabicyclo [3, 3, 1] -nonane dihydrochloride

30 parts of corn starch

55 parts of lactose

5 parts of polyvinylpyrrolidone

2 parts of magnesium stearate

3 parts of talcum powder

Total 115 parts

Preparation method

The active substance is mixed with corn starch and micronized lactose in a mixer.

The resulting mixture was thoroughly wetted with a 20% solution of polyvinylpyrrolidone ("Kollidon 25", from BASF) in deionized water. Additional deionized water was added if necessary. The wet granulation was passed through a 2mm screen, dried in a pan at 40 ℃ and then passed through a 1mm screen (Frewitt machine). After mixing the granules with magnesium stearate and talc, tablets weighing 115mg were compressed, thus containing 20mg of active substance per tablet.

Example 2:capsule composition

20 parts of N-isobutyl-N' -isopropyl-9, 9-pentamethylene-3, 7-diazabicyclo [3, 3, 1] nonane dihydrofumarate

20 portions of corn starch

45 parts of lactose

3 parts of polyvinylpyrrolidone

1.5 parts magnesium stearate

0.5 part of highly disperse silicic acid

90 portions of the total amount

Preparation method

The active substance is mixed with corn starch and micronized lactose in a mixer.

The resulting mixture was thoroughly wetted with a 20% solution of polyvinylpyrrolidone ("Kollidon 25", from BASF) in deionized water. Additional deionized water was added if necessary. The wet granulation was passed through a 1.6mm screen (Frewitt machine), dried in a pan at 40 deg.C, and then passed through a 1mm screen (Frewitt). After mixing the granules with magnesium stearate and highly dispersed silicic acid ("Aerosil 200", from Degussa), 90mg of each was filled into size 4 hard capsules using an automatic capsule filling machine, so that each capsule contained 20mg of active substance.

Example 3:ampoule composition (each ampoule)

5mg of N, N' -dicyclopropylmethyl-9, 9-tetramethylene-3, 7-diazabicyclo [3, 3, 1] nonane dihydrochloride

16mg sodium chloride

Adding water for injection to 2.0ml

Preparation method

The sodium chloride was dissolved in water for injection. The active substance is added and dissolved with stirring. Sufficient water for injection was added to the final volume. The mixture was passed through a 0.25.mu. membrane filter.

2.15ml portions are placed in brown glass ampoules and the ampoules are sealed. The ampoule is steam-sterilized at 121 ℃ for 30 minutes to give 2ml of injection containing 5mg of active substance.

Claims (10)

1. Use of a 3, 7-diazabicyclo [3, 3, 1] nonane compound, of a physiologically acceptable acid addition salt and/or of a solvate thereof, for the preparation of a pharmaceutical preparation for the treatment and/or prophylaxis of anti-arrhythmic events in male patients, preferably for converting a recent onset of atrial fibrillation (Afib) or flutter to a Normal Sinus Rhythm (NSR) in male patients.
2. 2. Use according to claim 1, wherein the 3, 7-diazabicyclo [3, 3, 1] nonane compound corresponds to formula I or a physiologically acceptable acid addition salt and/or solvate thereof:

   wherein

   R1 represents an alkyl group having 1 to 6 carbon atoms, an alkylene group having 3 to 6 carbon atoms and having one double bond not directly bonded to the nitrogen atom, a cycloalkylalkyl group having 4 to 9 carbon atoms, or a benzyl group,

   r2 represents lower alkyl, and

   r3 represents lower alkyl, or

   R2 and R3 together form an alkylene chain containing 3 to 6 carbon atoms, and

   r4 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 to 6 carbon atoms which has a double bond not directly linked to the nitrogen atom, a cycloalkylalkyl group having 4 to 9 carbon atoms, a group corresponding to formula a:

   wherein

   R5 represents hydrogen, halogen, lower alkyl or lower alkoxy, and

   z represents an alkylene chain containing 1 to 3 carbon atoms or a propyleneoyl chain having one double bond conjugated with a phenyl group,

   or a group according to formula b:

   wherein

   R6 represents hydrogen, halogen, lower alkyl or lower alkoxy, and

   r7 represents hydrogen, halogen, lower alkyl or lower alkoxy.
3. 3. Use according to claim 1, wherein R1 represents an alkyl group having 1 to 6 carbon atoms or a cycloalkylalkyl group having 4 to 7 carbon atoms.
4. 4. Use according to claim 1, wherein R4 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkylalkyl group having 4 to 7 carbon atoms or a group corresponding to formula b.
5. 5. Use according to claim 1, wherein R1 represents an alkyl group having 3 to 6 carbon atoms or a cycloalkylalkyl group having 4 to 7 carbon atoms, and R4 represents an alkyl group having 3 to 6 carbon atoms or a cycloalkylalkyl group having 4 to 7 carbon atoms.
6. 6. Use according to claim 1, wherein the 3, 7-diazabicyclo [3, 3, 1] nonane compound is a 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] nonane compound of formula I, wherein R2 and R3 together form an alkylene chain containing from 4 to 5 carbon atoms, and R1 and R4 independently of one another represent a linear or branched alkyl group having from 3 to 4 carbon atoms or a cyclopropylmethyl group, and physiologically acceptable acid addition salts and/or solvates thereof.
7. 7. Use according to claim 6, wherein said 3, 7-diazabicyclo [3, 3, 1] nonane compound is the fumarate salt of said 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] -nonane compound containing 1.5 moles of fumaric acid per mole of compound of formula I.
8. 8. Use according to claim 1, wherein the 3, 7-diazabicyclo [3, 3, 1] nonane compound is selected from the group consisting of N, N '-dicyclopropylmethyl-9, 9-tetramethylene-3, 7-diazabicyclo [3, 3, 1] nonane, N-isobutyl-N' -isopropyl-9, 9-pentamethylene-3, 7-diazabicyclo [3, 3, 1] nonane, and physiologically acceptable acid addition salts and/or solvates thereof.
9. 9. The use according to claim 8, wherein said 3, 7-diazabicyclo [3, 3, 1] nonane compound is a fumarate salt of N, N '-dicyclopropylmethyl-9, 9-tetramethylene-3, 7-diazabicyclo [3, 3, 1] nonane or N-isobutyl-N' -isopropyl-9, 9-pentamethylene-3, 7-diazabicyclo [3, 3, 1] nonane, which contains 1.5 moles of fumaric acid per mole of said 9, 9-alkylene-3, 7-diazabicyclo [3, 3, 1] -nonane compound.
10. 10. Use according to any one of claims 1, 5 and 7, wherein the 3, 7-diazabicyclo [3, 3, 1 jnonane compound is a hydrochloride salt.