CN1822833A - Use of 3,7-diazabicyclo not 3,3,1|nonane compounds for the treatment and/or prophylaxis of arrhythmic events in male human patients - Google Patents
Use of 3,7-diazabicyclo not 3,3,1|nonane compounds for the treatment and/or prophylaxis of arrhythmic events in male human patients Download PDFInfo
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Abstract
The present invention relates to the use of 3,7-diazabicyclo[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7diazabicyclo[3,3,1]nonane compounds, and most preferably to the use of tedisamil, and the physiologically acceptable acid addition salts and/or solvates thereof, for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients, preferably in conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients.
Description
The present invention relates to 3,7-diazabicyclo-[3,3,1] nonane compound, preferred 9,9-alkylidene-3,7-diazabicyclo [3,3,1]-nonane compound and most preferably tedisamil and the pharmaceutically-acceptable acid addition of described chemical compound and/or a kind of new medical usage of solvate.
From disclosed European patent EP 103,833 and corresponding US No.4,550,112 and Finnish patent FI 76,338 in as can be known formula I 9,9-alkylidene-3, the pharmaceutical active of 7-diazabicyclo nonane compound and they.Formula I chemical compound be in above-mentioned patent specification, describe and can be by 9 of the method preparation of wherein describing, 9-N, N '-quaternary 3, the subtribe of 7-diaza-dicyclo [3,3,1] nonane compound.Disclosed this chemical compound in the above-mentioned patent specification and had useful heart activity, particularly Chang Gui storage oxygen effect and, and very high physiology's toleration the effect of the heart rates and the rhythm of the heart.Therefore, even this chemical compound also demonstrates gratifying antiarrhythmic activity at low dosage.And unwanted negative interaction to cardiac contractile force is extremely low; Be that the arrhythmia of this chemical compound or the active ratio of secondary that heart prolongs active refractory stage and negativity muscular strength are good especially.
And people such as Burow are in U.S. Patent No. 5,164, and describe in 401: this chemical compound also has significant diuresis, has the excretory ratio of good sodium and potassium.
In addition,, described 3 in 732,7-diazabicyclo [3,3,1]-nonane compound, particularly 9,9-alkylidene-3, special salt of 7-diazabicyclo [3,3,1] nonane compound and preparation method thereof at US 5,324.Therefore, US 5,324, described the fumarate of described chemical compound in 732, and wherein every mole of this chemical compound contains 1.5 moles of fumaric acid.The document also provides at disclosed European patent EP 103,833 and corresponding US No.4, the reference of some conventional pharmacological activities of the formula I chemical compound of describing in 550,112.U.S. Patent No. 4,912,113 also provide new 3,7-diazabicyclo [3,3,1] nonane compound and pharmacological property thereof, and intermedium.Yet, propose that without any the patent of quoting any effect difference is arranged when the different sexes patient uses tedisamil.
Prior art patent document that what deserves to be mentioned is reference does not comprise any clinical data about the people, yet all pharmacology's evidences that provide are subjected to the restriction to the clinical Pretesting of animal such as rat and Canis familiaris L..In addition, some clinical preceding result of experiment have also been described in scientific literature.As people such as Fischbach " Tedisamil in a Chronic Canine Model ofAtrial Flutter " (Journal of Cardiovascular Pharmacology has been described, vol.34, No.2, in August, 1999, the the 212nd to 218 page), with " Conversion of AtrialFibrillation by the Experimentasl Antiarrhythmic DrugTedisamil in Two Canine Models " (Journal of CardiovascularElectrophsiology, vol.12, No.10, October calendar year 2001, the 1138th to 1144 page).Yet people such as Fischbach do not have to propose that any effect difference is arranged when the patient who gives different sexes uses tedisamil.People such as Opie discuss " Tedisamil in CoronoryDisease:Additional Benefits in Therapy of Atrial Fibrillation? " (Journal of Cardiovascular Pharmacology and Therapeutics, vol.8, No.supplement 1,2003, p.S33 to S37).They provide the rat heart of the coronary artery ligation that research exsomatizes and tedisamil on diastole and paradoxical expansion to exercise induced ischemic effect with to the data and the figure of the myocardial oxygen consumption effect of moving Canis familiaris L..Stated that also tedisamil has the ischemia resisting effect in to rat, rabbit, the Canis familiaris L. of running and human heart research; Yet people such as Opie have any effect difference when not having proposition to use tedisamil for the patient of different sexes.
In addition, people such as Julius Papp have described " Effects of Bertosamil onAtrial and Ventricular Treshold for Fibrillo-Flutter inComparison with Quinidine in Anaesthetized Cats " (Pharmaclogical Research, vol.25, No.supplement 2,1992, the the 156th to 157 page), with " Effects of Bertosamil on Rabbit Atrial andVentricular Transmembrane Potentials " (PharmaclogicalResearch, vol.25, No.supplement 2,1992, the 139 to 140 pages).Yet people such as Papp have any effect difference when also not having proposition to use tedisamil for the patient of different sexes.
Though Nicholas A.Flores is " Tedisamil Solvay " in Current Opinion in Investigational Drugs about the research topic of people's clinical stage, vol.2, No.1,2001, the the 97th to 103 page), but do not report that tedisamil has any effect difference to the patient of different sexes.
The purpose of this invention is to provide the new method that a kind of novel medical use or treatment need treat and/or prevent the antiarrhythmic male patient.
Another purpose of invention provides the new antiarrhythmic drug compositions of the activity curve with improvement that is used for the male patient.
The objective of the invention is by finding 3 surprisingly, 7-diazabicyclo-[3,3,1] nonane compound, preferred 9,9-alkylidene-3,7-diazabicyclo [3,3,1]-nonane compound, most preferably the pharmaceutically-acceptable acid addition of tedisamil and described chemical compound and/or solvate are particularly suitable for treating and/or preventing male patient's arrhythmia, preferably male patient's atrial fibrillation (Afib) or the nearest outbreak of fluttering are changed into normal sinus heart rate (NSR) reaches.According to others of the present invention; purpose reaches by a kind of antiarrhythmic pharmaceutical composition is provided; it comprises as described in the invention has 3 of antiarrhythmic activity to male patient's arrhythmia effective dose at least a; 7-diaza-dicyclo [3; 3,1] nonane compound.
Therefore, theme of the present invention is 3,7-diaza-dicyclo [3,3,1] nonane compound, its physiology goes up acceptable acid-addition salts and/or its solvate and is used for the treatment of and/or prevents male patient's arrhythmia in preparation, preferably male patient's atrial fibrillation (Afib) or the nearest outbreak of fluttering is changed into the purposes in the medicine of normal sinus heart rate (NSR).
The chemical compound that is suitable for male patient's this novel medical use is to meet 3 of formula I, and 7-diazabicyclo [3,3,1] nonane compound or its physiology go up acceptable acid-addition salts and/or solvate:
Wherein
R1 represent to contain 1 to 6 carbon atom alkyl, contain 3 to 6 carbon atoms the alkylidene with two keys that directly do not link to each other with nitrogen-atoms, contain the cycloalkyl-alkyl or the benzyl of 4 to 9 carbon atoms,
R2 represent low alkyl group and
R3 represents low alkyl group, or
R2 and R3 form together the alkylidene chain that contains 3 to 6 carbon atoms and
R4 represent to contain 1 to 6 carbon atom alkyl, contain 3 to 6 carbon atoms the alkenyl with two keys that directly do not link to each other with nitrogen-atoms, contain 4 to 9 carbon atoms cycloalkyl-alkyl, meet the group of formula a:
Wherein
R5 represent hydrogen, halogen, low alkyl group or lower alkoxy and
Z represents to contain the alkylidene chain of 1 to 3 carbon atom or an allylidene chain with conjugated pair of key of phenyl is arranged, or meets the group of formula b:
Wherein
R6 represent hydrogen, halogen, low alkyl group or lower alkoxy and
R7 represents hydrogen, halogen, low alkyl group or lower alkoxy.
The chemical compound that is particularly suitable for male patient's new medical usage according to the present invention is a formula I chemical compound, wherein the R1 cycloalkyl-alkyl representing to contain the alkyl of 1 to 6 carbon atom or contain 4 to 7 carbon atoms.In other preferred formula I chemical compound, substituent R 4 expression contain 1 to 6 carbon atom alkyl, contain the cycloalkyl-alkyl of 4 to 7 carbon atoms, or meet the group of formula b.
The preferred compound that is used for male patient's novel medical use according to the present invention is that formula I chemical compound and its physiology go up acceptable acid-addition salts and/or solvate, wherein R1 represents the cycloalkyl-alkyl that the cycloalkyl-alkyl that contains the alkyl of 3 to 6 carbon atoms or contain 4 to 7 carbon atoms and R4 represent to contain the alkyl of 3 to 6 carbon atoms or contain 4 to 7 carbon atoms.Described 3,7-diazabicyclo-[3,3,1] nonane compound can be 9 of formula I, 9-alkylidene-3,7-diazabicyclo [3,3,1] nonane compound, wherein R2 and R3 form the alkylidene chain that contains 4 to 5 carbon atoms together, and R1 and R4 represent to have straight chain or the branched-alkyl or the cyclopropyl methyl of 3-4 carbon atom independently of one another.
The preferred salt of this group chemical compound is 9,9-alkylidene-3, and the fumarate of 7-diazabicyclo [3,3,1] nonane compound, wherein every mole of formula I chemical compound contains 1.5 moles of fumaric acid.
Other preferred compound that is used for male patient's novel medical use according to the present invention is selected from N, N '-bicyclo-propyl-methyl-9,9-tetramethylene-3,7-diazabicyclo [3,3,1] nonane (tedisamil), N-isobutyl group-N '-isopropyl-9,9-pentamethylene-3,7-diazabicyclo [3,3,1] nonane and its physiology go up acceptable acid-addition salts and/or solvate.The preferred salt of this group chemical compound is N, N '-bicyclo-propyl methyl-9,9-tetramethylene-3,7-diazabicyclo [3,3,1] nonane (tedisamil) or N-isobutyl group-N '-isopropyl-9,9-pentamethylene-3,7-diazabicyclo [3,3,1] fumarate of nonane, wherein every mole described 9,9-alkylidene-3,7-diazabicyclo [3,3,1]-nonane compound contains 1.5 moles of fumaric acid.
Alternately, as 3, the acid-addition salts of 7-diazabicyclo [3,3,1] nonane compound---hydrochlorate also be very suitable for the male patient according to novel medical use of the present invention.
Particularly preferred 3,7-diazabicyclo [3,3,1] nonane compound is 9,9-alkylidene-3,7-diazabicyclo [3,3,1] nonane compound tedisamil and its physiology go up acid-addition salts and/or the solvate that is fit to, and these are to be used for preparation to be used for the treatment of and/or to prevent male patient's arrhythmia, preferably male patient's atrial fibrillation (Afib) or the nearest outbreak of fluttering are changed into the most preferred compound of the pharmaceutical preparation of normal sinus heart rate (NSR).If use the acid-addition salts of tedisamil, it can preferably use with the treatment male patient with the form of tedisamil hydrochlorate or with the form of tedisamil sesquialter fumarate according to the present invention.By European patent EP 103,833 acid-addition salts that go up to be fit to of other pharmacology of tedisamil as can be known.Therefore, the salt of mineral acid such as sulphuric acid or halogen acids, especially hydrochloric acid; Or organic acid, as the monocarboxylic acid or the dicarboxylic acids of lower aliphatic, as acetic acid, fumaric acid, tartaric acid, lactic acid, maleic acid, citric acid or salicylic salt; Or sulfonic acid, as low alkyl group sulfonic acid, as methanesulfonic acid, or the benzenesulfonic acid that randomly on phenyl ring, is replaced by halogen or low alkyl group, as the salt of right-toluenesulfonic acid, be suitable for going up acceptable acid-addition salts as the physiology of formula I chemical compound.
Surprisingly, except above-mentioned known conventional cardiac interaction property, have been found that and meet 3 of formula I, 7,9,9-quaternary 3,7-diazabicyclo [3,3,1] nonane compound is at male patient's arrhythmia, particularly male patient's atrial fibrillation (Afib) or the nearest outbreak of fluttering changed into the good action in the normal sinus heart rate (NSR).Formula I chemical compound is to male patient's antiarrhythmic effect preferably, particularly change male patient's atrial fibrillation (Afib) or the nearest outbreak of fluttering into normal sinus heart rate (NSR), can be by patient's clinical trial digital proof, this has proved 3,7-diazabicyclo [3,3,1] nonane compound, be fit to treat and/or prevent male patient's arrhythmia surprisingly as tedisamil and its acid-addition salts, preferably change male patient's atrial fibrillation (Afib) or the nearest outbreak of fluttering into normal sinus heart rate (NSR).
Clinical study design and result's explanation
A) patient's II phase clinical research
Analysis to people's original research shows that surprisingly curative effect has sex difference, when treating with tedisamil, compares with the women, and the male patient has higher number turnover.In addition, the male patient lacks than the safety problem that female patient occurs.Therefore, find surprisingly, compare with female patient, tedisamil to the male patient in antiarrhythmic therapy and particularly change in the normal sinus heart rate (NSR) specificity is arranged in nearest outbreak with atrial fibrillation (Afib).
This initial clinical research to the people be multicenter, double blinding, at random, placebo, the dosage group research of rising in succession change the curative effect and the safety of normal sinus heart rate rapidly in the patient who atrial fibrillation is arranged or flutter with the tedisamil of assessing intravenous administration.The active component that uses is a Tedisamil dihydrochloride.This research of design and in 35 to 40 of 3 to 4 countries, implementing in the heart in studying in the II phase.Research cycle: screening: reach 48 hours; Treatment (in the patient): single infusion 30 minutes of using; Safety is followed the trail of: (in the patient) continuous telemetering (telemetry) 24 hours and safety were followed the trail of 28 days.
The research purpose of elementary curative effect is to prove that to be determined at the percentage of patients that people's infusion is begun to change in any time in back 2.5 hours normal sinus heart rate (NSR) (at least 60 seconds) atrial fibrillation/tedisamil of any dosage all is better than placebo in fluttering stopping.The purpose of secondary curative effect is to measure tedisamil to compare with placebo, begins back 2.5 hours in venoclysis, keeps the percentage of patients of sinus rate; Measure tedisamil and compare, began back 24 hours, keep the percentage of patients of sinus rate in venoclysis with placebo; Measure tedisamil and compare the fringe time after infusion begins with placebo; Compare with placebo with the mensuration tedisamil, dosage-and plasma concentration-reaction relation.Safety purpose: measure safety and toleration that tedisamil is compared with placebo.
Application is used to study people's following methodology: multicenter, double blinding, at random, dosage group placebo, that rise in succession studies curative effect and the safety that the tedisamil of assessing intravenous administration is compared with placebo.The medicine that infusion is studied reached a half-value dose and reached second half dosage in remaining 20 minute more than 30 minutes in 10 minutes.First group of patient accepts 0.4mg/kg body weight (bw), with 0.2mg/kg bw infusion, continues with 0.2mg/kg bw infusion in 20 minutes in 10 minutes.Only assess (double blinding) predose and find safe after, the dosage 0.6mg/kg bw (infusion 0.3mg/kg bw in 10 minutes, continuation infusion 0.3mg/kg bw in 20 minutes) that following portion is higher.Three phases can add higher dosage.In infusion (at 10 and 30 minutes), changing normal sinus heart rate into, when infusion began back 24 hours and recur, the blood drug level of assessment tedisamil.
The number of subjects of plan: 330 of picked at random (110 patients of every dosage group)
Diagnosis and the main standard of drawing a conclusion:
Atrial fibrillation in＞3 hours and＜48 hours or flutter the conduct first time or recurrence outbreak.
Test products, dosage and pattern:
Tedisamil (0.4mg/kg body weight)
Tedisamil (0.6mg/kg body weight)
All be the dosage of intravenous administration.
With reference to treatment, dosage and pattern:
Venoclysis in 30 minutes gives placebo (carrier).
Treatment cycle:
Total infusion time is 30 minutes, wherein half-value dose infusion and second half dosage infusion in remaining 20 minutes in 10 minutes.
Evaluation criteria:
1) curative effect:
Elementary curative effect: any time after the medicine that the beginning infusion is studied in 2.5 hours is changed the percentage of patients of normal sinus heart rate (at least 60 seconds) into.
Secondary curative effect: the percentage of patients that begins 2.5 and 24 hours the NSR in back at infusion; The time that changes; Dosage-and concentration-response relationship.
2) safety:
Health check-up, ECG, lodging supervision, vital sign, Laboratory Evaluation and untoward reaction in 24 hours.
Statistical method:
Assess all efficacy variables of atrial fibrillation patient and atrial flutter patient respectively.Treatment group and center are used the logarithm regression model of being with the factor, the percentage ratio that changes in the relatively treatment group.Treatment group and center are used Cox proportional hazards model withfactors, the fringe time in the relatively treatment group.Measure dose-response and concentration-response relationship with descriptive statistics.
For the calculating of patient's numeral, do following hypothesis:
1. to the atrial fibrillation patient, the percentage ratio that in placebo group, (begins any time in back 2.5 hours) and change into normal sinus heart rate at infusion be 20% and also clinical relevant difference be 20%.
2. to the atrial flutter patient, the percentage ratio that changes normal sinus heart rate in placebo group into is 10%, and clinical relevant difference is 40%.
Carry out the interim analysis of curative effect midway with outside statistics in first and second stages.Purpose is that dosage when used tedisamil when invalid, finishes this stage in that stage.Technically, each interim analysis is the calculating of expectation ability, is used for the elementary efficacy variables of comparison tedisamil and placebo.In addition, (if applicable) carries out double blinding safety research and efficacy analysis simultaneously when each stage finishes.
B) people's III phase clinical research
To the analysis confirmation of people's secondary research the discovery of research for the first time, as the sex difference about curative effect, when treating with tedisamil, the male patient is than women's number turnover height.
In this secondary clinical research be to the people multicenter, double blinding, at random, the parallel design studies (Parallel Design Study) of placebo changes the curative effect and the safety of normal sinus heart rate rapidly into to the experimenter of the nearest outbreak that atrial fibrillation arranged or flutter with the tedisamil sesquialter fumarate of assessment intravenous administration.
Used active component is a tedisamil sesquialter fumarate.Design this research when studying and enforcement in the heart in 30 to 40 of 5 countries in the II phase.Research cycle: screening: reach 48 hours; Treatment: (in the patient) single infusion 30 minutes of using; Safety is followed the trail of: (in the patient) continuous telemetering 24 hours and safety were followed the trail of 28 days.
Research people's the purpose of elementary curative effect is to prove recently with the percentage of measuring the experimenter who changes in infusion begins any time in back 2.5 hours changing into rapidly in the normal sinus heart rate (at least 60 seconds) that the tedisamil sesquialter fumarate of any dosage is better than placebo.The purpose of secondary curative effect is to be determined at venoclysis to begin any time of back in 2.5 hours and change normal sinus heart rate into and compare the percentage ratio that begins the experimenter of back 2.5 hours normal sinus heart rates at infusion at tedisamil sesquialter fumarate with placebo; Being determined at venoclysis begins any time of back in 2.5 hours and changes normal sinus heart rate into and compare the percentage ratio that begins the experimenter of back 24 hours normal sinus heart rates at infusion at tedisamil sesquialter fumarate with placebo; Be determined at venoclysis and begin that any time in back 2.5 hours is changed normal sinus heart rate into and the experimenter's of the normal sinus heart rate of leaving hospital percentage ratio; Measure tedisamil sesquialter fumarate and compare the time of after infusion begins, changing normal sinus heart rate into placebo; The dosage that mensuration tedisamil sesquialter fumarate is compared with placebo-and concentration-response relationship; Compare DC cardioversion institute energy requirement with placebo with mensuration tedisamil sesquialter fumarate.Safety purpose: measure safety and toleration that tedisamil sesquialter fumarate is compared with placebo.
Use following methodology: multicenter, double blinding, at random, placebo-controlled study assesses curative effect and the safety that the tedisamil sesquialter fumarate of intravenous administration is compared with placebo.Infusion was studied medicine more than 30 minutes, reached a half-value dose and reached second half dosage in 10 minutes in remaining 20 minutes.
Experimenter's random assortment is to accept:
-every kg body weight (bw) 0.32mg tedisamil free alkali (0.16mg/kg bw in 10 minutes, 0.16mg/kg bw in 20 minutes subsequently); Or
-every kg bw 0.48mg tedisamil free alkali (0.24mg/kgbw in 10 minutes, 0.24mg/kg bw in 20 minutes subsequently); Or
-every kg bw 0.64mg tedisamil free alkali (0.32mg/kgbw in 10 minutes, 0.32mg/kg bw in 20 minutes subsequently); Or
-infusion placebo 30 minutes.
The number of subjects of plan:
The atrial fibrillation experimenter of 212 picked at random (53 experimenters of each treatment group).
These experimenters are elementary target groups.In addition, in the scope of this research, note down 80 (20 of each treatment groups) experimenters that are considered to atrial flutter.
Yet,,, also can finish research though do not note down the experimenter of all atrial flutters if reach the atrial fibrillation experimenter's of plan numeral.
Diagnosis and the main standard of drawing a conclusion:
Atrial fibrillation or flutter the conduct first time or recurrence outbreak in＞3 hours and＜45 days.
Test products, the dosage of administration and pattern:
-tedisamil free alkali 0.32mg/kg body weight (is equivalent to 0.51mg/kg tedisamil sesquialter fumarate and 0.4mg/kg Tedisamil dihydrochloride
-tedisamil free alkali 0.48mg/kg body weight (is equivalent to 0.77mg/kg tedisamil sesquialter fumarate and 0.6mg/kg Tedisamil dihydrochloride
-tedisamil free alkali 0.64mg/kg body weight (is equivalent to 1.02mg/kg tedisamil sesquialter fumarate and 0.8mg/kg Tedisamil dihydrochloride
Give described dose through vein.
The dosage of tedisamil refers to the tedisamil free alkali in the experimental design.
With reference to treatment, dosage and pattern:
The similar tedisamil intravenous infusion administration of placebo (carrier) 30 minutes.
The treatment phase:
Total infusion time is 30 minutes, infusion one half-value dose in 10 minutes, and remaining second half dosage of infusion in 20 minutes.
Evaluation criteria:
1) curative effect:
Elementary curative effect: the percentage ratio that in the infusion of drug that is studied begins any time in back 2.5 hours, changes the experimenter of normal sinus heart rate (at least 60 seconds) into.
The middle rank curative effect: change normal sinus heart rate and the experimenter's who leaves hospital percentage ratio in any time and 24 hours that infusion begins in back 2.5 hours, fringe time, dosage-and concentration-response relationship and DC cardioverting energy.
2) safety:
Health check-up, ECG, lodging supervision, vital sign, Laboratory Evaluation and untoward reaction in 24 hours.
Statistical method:
With the percentage ratio that changes in the relatively treatment group of (Pearson) variance statistical method.With the time that changes in the relatively treatment group of sequence check.With descriptive statistics check dose-response and concentration-response relationship and the required energy of DC transformation.
Analyze the experimenter of atrial fibrillation and atrial flutter respectively.In addition, with these two kinds of crowd's fractional analysis.All being that experimenter crowd's the analysis of atrial flutter is as monitoring.
Table I: the nearest outbreak (Afib) of atrial fibrillation changes NSR into
Change NSR in any time that infusion begins in back 2.5 hours.
ITT patient's sample; The patient who gets rid of the DC cardioversion.
| Sex (people) | Anti-arrhythmia treatment | |||
| Tedisamil | Placebo | |||
| 0.4mg/kg | 0.6mg/kg | |||
| Atrial fibrillation | The male | 18/35(51.4％) | 18/26(69.2％) | 2/24(8.3％) |
| The women | 6/17(35.3％) | 6/16(37.5％) | 2/22(9.1％) | |
| Atrial flutter | The male | 1/7(14.3％) | 1/5(20.0％) | 0/10 |
| The women | 0/2 | 2/6(33.3％) | 0/3 | |
| All | The male | 19/42(45.2％) | 19/31(61.3％) | 2/34(5.9％) |
| The women | 6/19(31.6％) | 8/22(36.4％) | 2/25(8.0％) | |
Table II: the nearest outbreak of atrial fibrillation (Afib) changes NSR into
Change NSR in any time that infusion begins in back 2.5 hours.
The patient of atrial fibrillation
ITT patient's sample; The patient who gets rid of the DC cardioversion.
| Sex (people) | Age | Anti-arrhythmia treatment | ||
| Tedisamil | Placebo | |||
| 0.4mg/kg | 0.6mg/kg | |||
| The male | ＜65 years old | 10/20(50.0％) | 13/18(72.2％) | 1/14(7.1％) |
| ＞=65 years old | 8/15(51.4％) | 5/8(62.5％) | 1/10(10％) | |
| Amount to | 18/35(51.4％) | 18/26(69.2％) | 2/24(8.3％) | |
| The women | ＜65 years old | 2/5(40.0％) | 1/3(33.3％) | 1/5(20.0％) |
| ＞=65 years old | 4/12(33.3％) | 5/13(38.5％) | 1/17(5.9％) | |
| Amount to | 6/17(35.3％) | 6/16(37.5％) | 2/22(9.1％) | |
Table III: the nearest outbreak of atrial fibrillation (Afib) changes NSR into
Change NSR in any time that infusion begins in back 2.5 hours.
ITT patient's sample; The patient who gets rid of the DC cardioversion.
| Sex (people) | Anti-arrhythmia treatment | |||
| Tedisamil | Placebo | |||
| 0.4mg/kg | 0.6mg/kg | |||
| Atrial fibrillation | The male | 18/35(51.4％) | 18/26(69.2％) | 2/24(8.3％) |
| The p-value, ChiSq (contrast placebo) | ＜0.001 | ＜0.001 | ||
| The women | 6/17(35.3％) | 6/16(37.5％) | 2/22(9.1％) | |
| The p-value, ChiSq (contrast placebo) | ＜0.045 | ＜0.034 | ||
| Atrial flutter | The male | 1/7(14.3％) | 1/5(20.0％) | 0/10 |
| The p-value, ChiSq (contrast placebo) | 0.218 | 0.143 | ||
| The women | 0/2 | 2/6(33.3％) | 0/3 | |
| The p-value, ChiSq (contrast placebo) | - | 0.257 | ||
| All | The male | 19/42(45.2％) | 19/31(61.3％) | 2/34(5.9％) |
| The p-value, ChiSq (contrast placebo) | ＜0.001 | ＜0.001 | ||
| The women | 6/19(31.6％) | 8/22(36.4％) | 2/25(8.0％) | |
| The p-value, ChiSq (contrast placebo) | ＜0.045 | ＜0.018 | ||
The antiarrhythmic male patient is clearer and more definite than the female patient of antiarrhythmic therapy to the reaction with tedisamil treatment as can be seen from these data, and especially changes in the normal sinus heart rate (NSR) in the nearest outbreak (Afib) of atrial fibrillation.
Special surprisingly as to the people above-mentioned result of study proved, in treating and/or preventing male patient's arrhythmia, especially change among the NSR in nearest outbreak male patient's atrial fibrillation (Afib), 3,7-diazabicyclo-[3,3,1] nonane compound, preferred 9,9-alkylidene-3,7-diazabicyclo [3,3,1]-nonane compound and most preferably tedisamil and pharmaceutically-acceptable acid addition and/or solvate to male patient's effect, because before two kinds of sexes are all used the big quantity research of tedisamil, do not observe the curative effect difference of this human sex, especially in the description of prior art, in preclinical zooscopy, do not observe the specificity of this sex yet.
In to patient's research, find the curative effect of tedisamil, from the result, can sum up tedisamil---similar 3,7-diazabicyclo-[3,3,1] nonane compound, preferred 9,9-alkylidene-3,7-diazabicyclo [3,3,1]-nonane compound and tedisamil itself most preferably, with its acid-addition salts, show the number turnover height of male patient than female patient.Above-mentioned overtime prolongation infusion is not produced higher number turnover.From the result, can sum up safety: observed nearly all people that TdP (Torsade dePoint) (torsive ventricular tachycardia) is arranged is a female patient in the 30min of administration.Has only the 0.72 demonstration TdP of male patient in 3114 researchs with high dose.
According to the present invention,, can comprise 3 as therapeutic agent, 7-diazabicyclo-[3,3,1] nonane compound, preferred 9,9-alkylidene-3,7-diazabicyclo [3,3,1]-nonane compound, and most preferably tedisamil and pharmaceutically-acceptable acid addition and/or solvate, with the pharmaceutical auxiliary agent and/or the carrier of routine, in the solid or liquid pharmaceutical formulation of administration of human.The example of the solid preparation that can be taken orally, as tablet, coated tablet, capsule, powder or granule, or as the suppository of selecting.These preparations can comprise conventional inorganic and/or organic carrier pharmaceutically, as Pulvis Talci, lactose or starch and conventional pharmaceutical auxiliary agent, as the disintegrating agent of lubricant or tablet.Liquid preparation, as 3,7-diazabicyclo-[3,3,1] nonane compound, preferred 9,9-alkylidene-3,7-diazabicyclo [3,3,1]-nonane compound, and the most preferably suspensoid or the Emulsion of tedisamil and pharmaceutically-acceptable acid addition and/or its solvate, can comprise diluent commonly used, Ru Shui, oil and/or suspensoid are as Polyethylene Glycol etc.Can additionally add other auxiliary agent, as antiseptic, correctives etc.
3,7-diazabicyclo-[3,3,1] nonane compound, preferred 9,9-alkylidene-3,7-diazabicyclo [3,3,1]-nonane compound, most preferably tedisamil and pharmaceutically-acceptable acid addition and/or its solvate can mix and prepare with pharmaceutically auxiliary agent and/or carrier with known method.Be used to prepare the solid drug forms of administration of human, 3,7-diazabicyclo-[3,3,1] nonane compound, preferred 9,9-alkylidene-3,7-diazabicyclo [3,3,1]-nonane compound and tedisamil most preferably, with pharmaceutically-acceptable acid addition and/or its solvate, can mix with auxiliary agent and/or carrier and can wet method or dry granulation with the method for routine.This granule or powder can directly incapsulate interior or examine with conventional method tablet forming.If desired, these preparations can be with known method coating.
Embodiment
Described in the following example 1 to 3 according to the present invention and contained the pharmaceutical preparation of formula I active substance and the preparation of this pharmaceutical preparation.Following each embodiment has illustrated the preparation of the pharmaceutical preparation that contains Tedisamil dihydrochloride.The pharmaceutical preparation that contains tedisamil sesquialter fumarate can obtain with similar method.
Embodiment 1:Tablet composition:
20 parts of N, N '-bicyclo-propyl methyl-9,9-tetramethylene-3,7-diazabicyclo [3,3,1]-nonane dihydrochloride
30 parts of corn starchs
55 parts of lactose
5 parts of polyvinylpyrrolidones
2 parts of magnesium stearate
3 parts of Pulvis Talci
115 parts of total amounts
Preparation method
Active substance is mixed in blender with corn starch and micronized lactose.
20% polyvinylpyrrolidone (" Kollidon25 " is from the BASF) solution that the mixture that obtains is used in the deionized water is fully moistening.If desired, add deionized water in addition.This wet granular by the 2mm screen cloth, in 40 ℃ of dryings, is passed through 1mm screen cloth (Frewitt machine) then in dish.This granule with after magnesium stearate and Pulvis Talci are mixed, is pressed into the tablet of heavy 115mg, and therefore, every contains the 20mg active substance.
Embodiment 2:Capsule composition
20 parts of N-isobutyl group-N '-isopropyls-9,9-pentamethylene-3,7-diazabicyclo [3,3,1] nonane dihydro fumarate
20 parts of corn starchs
45 parts of lactose
3 parts of polyvinylpyrrolidones
1.5 part magnesium stearate
0.5 the silicic acid of part high degree of dispersion
90 parts of total amounts
Preparation method
Active substance is mixed in blender with corn starch and micronized lactose.
20% polyvinylpyrrolidone (" Kollidon25 " is from the BASF) solution that the mixture that obtains is used in the deionized water is fully moistening.If desired, add deionized water in addition.This wet granular by 1.6mm screen cloth (Frewitt machine), in 40 ℃ of dryings, is passed through 1mm screen cloth (Frewitt) then in dish.After the silicic acid (" Aerosil 200 " are from Degussa) of this granule and magnesium stearate and high degree of dispersion mixed, every 90mg was with the automatic capsule filler hard capsule of packing into No. 4, so each capsule contains the 20mg active substance.
Embodiment 3:Ampoule compositions (each ampoule)
5mg N, N '-bicyclo-propyl methyl-9,9-tetramethylene-3,7-diazabicyclo [3,3,1] nonane dihydrochloride
16mg sodium chloride
Water for injection adds to 2.0ml
Preparation method
Sodium chloride is dissolved with water for injection.Active substance is added and stirring and dissolving.The water for injection that adds capacity is to final volume.This mixture is passed through the 0.25.mu. membrane filter.
Every part of 2.15ml is packed in the brown glass ampoule, and ampoule is sealed.This ampoule 121 ℃ of steam sterilizations 30 minutes, is obtained containing the 2ml injection of 5mg active substance.
Claims (10)
1.3,7-diazabicyclo [3,3,1] nonane compound, its physiology goes up acceptable acid-addition salts and/or solvate and is used for the treatment of and/or prevents male patient's arrhythmia in preparation, preferably male patient's atrial fibrillation (Afib) or the nearest outbreak of fluttering is changed into the purposes in the pharmaceutical preparation of normal sinus heart rate (NSR).
2. according to the purposes of claim 1, wherein 3,7-diazabicyclo [3,3,1] nonane compound meets formula I or its physiology goes up acceptable acid-addition salts and/or solvate:
Wherein
R1 represent to contain 1 to 6 carbon atom alkyl, contain 3 to 6 carbon atoms the alkylidene with two keys that directly do not link to each other with nitrogen-atoms, contain the cycloalkyl-alkyl or the benzyl of 4 to 9 carbon atoms,
R2 represent low alkyl group and
R3 represents low alkyl group, or
R2 and R3 form together the alkylidene chain that contains 3 to 6 carbon atoms and
R4 represent to contain 1 to 6 carbon atom alkyl, contain 3 to 6 carbon atoms the alkenyl with two keys that directly do not link to each other with nitrogen-atoms, contain 4 to 9 carbon atoms cycloalkyl-alkyl, meet the group of formula a:
Wherein
R5 represent hydrogen, halogen, low alkyl group or lower alkoxy and
Z represents to contain the alkylidene chain of 1 to 3 carbon atom or an allylidene chain with conjugated pair of key of phenyl arranged,
Or meet the group of formula b:
Wherein
R6 represent hydrogen, halogen, low alkyl group or lower alkoxy and
R7 represents hydrogen, halogen, low alkyl group or lower alkoxy.
3. according to the purposes of claim 1, the R1 cycloalkyl-alkyl representing to contain the alkyl of 1 to 6 carbon atom or contain 4 to 7 carbon atoms wherein.
4. according to the purposes of claim 1, wherein R4 represent to contain 1 to 6 carbon atom alkyl, contain the cycloalkyl-alkyl of 4 to 7 carbon atoms or meet the group of formula b.
5. according to the purposes of claim 1, wherein R1 represents the cycloalkyl-alkyl that the cycloalkyl-alkyl that contains the alkyl of 3 to 6 carbon atoms or contain 4 to 7 carbon atoms and R4 represent to contain the alkyl of 3 to 6 carbon atoms or contain 4 to 7 carbon atoms.
6. according to the purposes of claim 1, wherein said 3,7-diazabicyclo [3,3,1] nonane compound is 9 of formula I, 9-alkylidene-3,7-diazabicyclo [3,3,1] nonane compound and physiology thereof go up acceptable acid-addition salts and/or solvate, wherein R2 and R3 form straight chain or branched-alkyl or the cyclopropyl methyl that the alkylidene chain that contains 4 to 5 carbon atoms and R1 and R4 represent to have 3-4 carbon atom independently of one another together.
7. according to the purposes of claim 6, wherein said 3,7-diazabicyclo [3,3,1] nonane compound is that every mole of formula I chemical compound contains 1.5 moles fumaric acid described 9,9-alkylidene-3, the fumarate of 7-diazabicyclo [3,3,1]-nonane compound.
8. according to the purposes of claim 1, wherein said 3,7-diazabicyclo [3,3,1] nonane compound is selected from N, N '-bicyclo-propyl methyl-9,9-tetramethylene-3,7-diazabicyclo [3,3,1] nonane, N-isobutyl group-N '-isopropyl-9,9-pentamethylene-3,7-diazabicyclo [3,3,1] nonane and its physiology go up acceptable acid-addition salts and/or solvate.
9. according to the purposes of claim 8, wherein said 3,7-diazabicyclo [3,3,1] nonane compound is N, N '-bicyclo-propyl methyl-9,9-tetramethylene-3,7-diazabicyclo [3,3,1] nonane or N-isobutyl group-N '-isopropyl-9,9-pentamethylene-3,7-diazabicyclo [3,3,1] fumarate of nonane, every mole is described 9,9-alkylidene-3,7-diazabicyclo [3,3,1]-nonane compound contains 1.5 moles of fumaric acid.
10. according to claim 1,5 and 7 each purposes, wherein said 3,7-diazabicyclo [3,3,1] nonane compound is a hydrochlorate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03102243.7 | 2003-07-21 | ||
| EP03102243 | 2003-07-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1822833A true CN1822833A (en) | 2006-08-23 |
Family
ID=34112472
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200480019884XA Pending CN1822833A (en) | 2003-07-21 | 2004-07-19 | Use of 3,7-diazabicyclo not 3,3,1|nonane compounds for the treatment and/or prophylaxis of arrhythmic events in male human patients |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1648456A1 (en) |
| JP (1) | JP2006528155A (en) |
| CN (1) | CN1822833A (en) |
| AU (1) | AU2004260624A1 (en) |
| BR (1) | BRPI0412247A (en) |
| CA (1) | CA2533492A1 (en) |
| MX (1) | MXPA06000796A (en) |
| WO (1) | WO2005011690A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3275870B1 (en) | 2011-05-10 | 2020-02-05 | Gilead Sciences, Inc. | Fused heterocyclic compounds as ion channel modulators |
| NO3175985T3 (en) | 2011-07-01 | 2018-04-28 | ||
| TWI549944B (en) | 2011-07-01 | 2016-09-21 | 吉李德科學股份有限公司 | Fused heterocyclic compounds as ion channel modulators |
| WO2014134419A1 (en) * | 2013-03-01 | 2014-09-04 | Gilead Sciences, Inc. | Use of ikach blockers for the treatment of cardiac diseases |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3234697A1 (en) * | 1982-09-18 | 1984-03-22 | Kali-Chemie Pharma Gmbh, 3000 Hannover | NEW DIAZABICYCLO (3,3,1) NONANA |
| PT88381B (en) * | 1987-09-09 | 1995-07-06 | Kali Chemie Pharma Gmbh | PROCESS FOR THE PREPARATION OF NEW COMPOUNDS 3,7-DIAZABICYCLO (3,3,1) NONANO, AND OF PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS |
| DE4139763A1 (en) * | 1991-12-03 | 1993-06-09 | Kali-Chemie Pharma Gmbh, 3000 Hannover, De | CRYSTALLINE FUMAR ACID SALTS OF 9,9-ALKYLENE-3,7-DIAZABICYCLONONAN COMPOUNDS AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| TW200418468A (en) * | 2002-11-18 | 2004-10-01 | Solvay Pharm Gmbh | Liquid pharmaceutical formulations containing 3,7-diazabicyclo[3,3,1]nonane compounds and method of treatments relating to anti-arrhytmic events |
-
2004
- 2004-07-19 CA CA002533492A patent/CA2533492A1/en not_active Abandoned
- 2004-07-19 BR BRPI0412247-0A patent/BRPI0412247A/en not_active Application Discontinuation
- 2004-07-19 AU AU2004260624A patent/AU2004260624A1/en not_active Abandoned
- 2004-07-19 JP JP2006520832A patent/JP2006528155A/en not_active Withdrawn
- 2004-07-19 CN CNA200480019884XA patent/CN1822833A/en active Pending
- 2004-07-19 EP EP04742001A patent/EP1648456A1/en not_active Withdrawn
- 2004-07-19 WO PCT/EP2004/051532 patent/WO2005011690A1/en not_active Application Discontinuation
- 2004-07-19 MX MXPA06000796A patent/MXPA06000796A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU2004260624A1 (en) | 2005-02-10 |
| EP1648456A1 (en) | 2006-04-26 |
| WO2005011690A1 (en) | 2005-02-10 |
| CA2533492A1 (en) | 2005-02-10 |
| MXPA06000796A (en) | 2006-04-07 |
| BRPI0412247A (en) | 2006-09-19 |
| JP2006528155A (en) | 2006-12-14 |
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