Method for treating neurocardiogenic syncope

The present invention relates to methods for treating neurocardiogenic syncope. The method involves administering to a patient an effective amount of a compound having the formula: ##STR1## wherein R.sub.1, R.sub.2 and R.sub.5 are each selected from the group consisting of hydrogen and lower alkyl; and R.sub.3 and R.sub.4 are each selected from the group consisting of hydrogen, halogen, lower alkyl, nitro, amino, trifluoromethyl, and lower acylamino; at least one of R.sub.3 and R.sub.4 being a nitrogen containing group, or a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION 
The present invention relates to methods for treating neurocardiogenic 
syncope, and more particularly to the use of benzodiazepines such as 
clonazepam to treat such a disorder. 
BACKGROUND OF THE INVENTION 
Throughout this application various publications are referenced, many in 
parenthesis. Full citations for these publications are provided at the end 
of the Detailed Description. The disclosures of these publications in 
their entireties are hereby incorporated by reference in this application. 
Neurocardiogenic syncope is a collective term used to describe the clinical 
syndromes of syncope that result from inappropriate, and often excessive, 
autonomic reflex activity, and manifest as abnormalities in the control of 
vascular tone and heart rate. These include carotid sinus syndrome, 
vasovagal syncope, and the syndromes of cough, deglutition, and 
micturition syncope (Sutton and Petersen 1995). "Syncope" refers to the 
sudden transient loss of consciousness (fainting) associated with the 
inability to maintain postural tone. "Pre-syncope" refers to premonitory 
signs and symptoms of imminent syncope, including pallor, sighing, 
hyperventilation, nausea, diaphoresis, blurred vision, impaired hearing, 
feeling of unawareness, and palpitations. Syncope can also occur without 
such premonitory signs and symptoms. 
Neurocardiogenic syncope can be induced by a variety of conditions, 
including but not limited to, auditory and visual stimuli, hypovolemia, 
severe anxiety, situations which produce sympatho-adrenal discharge with 
resultant increase in myocardial contractility, and on occasion it may 
occur without apparent precipitating factors. Vasovagal syncope is a 
condition marked by a sudden drop in heart rate and/or blood pressure, 
resulting in fainting. It is not only unpleasant for a patient, but 
potentially dangerous, as fainting may lead to injuries from falls. 
Vasovagal syncope is generally precipitated by fear, emotional stress, or 
pain. For example, patients with blood-injury phobia can suffer vasovagal 
syncope in response to common venipuncture (Lipton and Forstarer 1993). 
Lipsitz et al. reported that among elderly patients (75 years or older) 
there is a 6% annual incidence of unexplained syncope with recurrence rate 
of 30%. Causes of syncope include situational syncope (1-8%), orthostatic 
hypotension (4-12%), drug-induced syncope (2-9%), organic cardiac disease 
(3-11%), arrhythmias 5-30%), vasovagal (1-29%), and unknown (38-47%). 
Classically, neurocardiogenic syncope is diagnosed by exclusion of other 
diagnoses, as well as by reproducing the clinical signs and symptoms by 
utilization of the head up tilt test. During this test while the patient 
is supported on a bed, the bed is tilted to 35.degree. for three minutes 
and then up to 70.degree. for 45 minutes or until pre-syncope occurs. A 
positive test for neurocardiogenic syncope is one that causes symptomatic 
hypotension, bradycardia, or both. A normal physiologic,response to head 
up tilt test (negative test) consists of an increase in heart rate, 
increase in diastolic pressure, and slight decrease in systolic pressure 
with little or no change in mean arterial pressure. The head up tilt test 
has gained broad acceptance as a reliable diagnostic method for the 
assessment of patients with recurrent unexplained syncope (Fitzpatrick et 
al. 1989; Fitzpatrick et al. 1991a; Fouad et al. 1993; Grubb et al. 1992a; 
Grubb et al. 1992b; Raviele et al. 1990; Grubb et al. 1993; Grubb et al. 
1991; Chen et al.) Other diagnostic methods include prolonged 
electrocardiographic monitoring and electrophysiologic studies. 
Once the diagnosis of syncope is reached, there is no consensus on the most 
appropriate treatment. In this respect, efficacy of existing drug therapy 
in preventing recurrence of symptoms in patients is not entirely clear, 
and controversies exist regarding the need to confirm the effects of 
pharmacological interventions. Natale et al. (1995) assessed different 
therapeutic approaches to patients diagnosed by the head up tilt test. Of 
303 patients, 44 received empiric therapy, 210 were treated with 
medications proven effective during repeated head up tilt testing, and 49 
refused or discontinued medical therapy. Among the patients treated 
according to head up tilt guided therapy, 130 were on beta blockers, 35 on 
theophylline, 10 on ephedrine, 31 on disopyramide, and 4 on miscellaneous 
regimens. Empiric treatment consisted of beta blockers in 37 of 44 
patients and other drugs in the remaining patients. During the follow-up, 
recurrence of symptoms was experienced in 12 (6%) of the 210 patients 
receiving the head up tilt guided therapy, 16 (36%) of 44 in the empiric 
therapy group, and 33 (67%) of 49 in the no therapy group. Recurrence of 
symptoms in patients on empiric or no therapy was significantly more 
frequent as compared to the head up tilt guided therapy group. 
Sra et al. (1993b) compared the efficacy of permanent cardiac pacing in 
patients with neurocardiogenic syncope associated with bradycardia or 
asystole with that of oral drug therapy in the prevention of hypotension 
and syncope during head up tilt testing. Among 70 patients with a history 
of syncope in whom hypotension and syncope could be provoked during head 
up tilt testing, 22 had bradycardia (a heart rate &lt;60 beats per minute, 
with a decline in the rate by at least 20 beats per minute) or asystole 
along with hypotension during testing. Head up tilt testing was repeated 
during atrioventricular sequential pacing (in 20 patients with sinus 
rhythm) or ventricular pacing in 2 patients with atrial fibrillation). 
Regardless of the results obtained during artificial pacing, all the 
patients subsequently had upright tilt testing repeated during therapy 
with oral metoprolol, theophylline, or disopyramide. During the initial 
tilt test, 6 patients had asystole and 16 had bradycardia along with 
hypotension. Despite artificial pacing, the mean arterial pressure during 
head up tilt testing still fell significantly. Five (5) patients had 
syncope, and 15 had presyncope. By contrast, 19 patients who later 
received only medical therapy (metoprolol in 10, theophylline in 3, and 
disopyramide in 6), 2 patients who received both metoprolol and 
atrioventricular sequential pacing, and 1 patient who received only 
atrioventricular sequential pacing, had negative head up tilt tests. After 
a median follow-up of 16 months, 18 of the 19 patients who were treated 
with drugs alone (94%) remained free of recurrent syncope or pre-syncope, 
whereas the patient treated only with permanent dual-chamber pacemaker had 
recurrent syncope. Thus, drug therapy was more effective than artificial 
pacing. 
Therapies for neurocardiogenic syncope have included volume expansion, beta 
blockers, transdermal scopolamine (Abi-Samra et al. 1988), Norpace or 
disopyramide (Milstein et al. 1990), Florinef 
(mineralocorticoids/glucocorticoids), and cardiac pacing (Kenny et al. 
1986; Fitzpatrick et al. 1991b; Sra et al. 1993b). Cardiac pacing as a 
treatment of vasovagal syncope is disclosed in U.S. Pat. No. 5,501,701 of 
Markowitz and Hess and in U.S. Pat. No. 5,284,491 of Sutton et al. 
For general discussions of diagnosis, mechanisms, and/or treatment of 
neurocardiogenic syncope, see Sra et al. 1993a; Kosinski et al. 
1995;Kapoor 1992;and Natale et al. 1995. 
Patients with neurocardiogenic syncope may, on occasions, be prevented from 
driving or from being in any place by themselves where if they faint they 
could endanger their life or the lives of others. With the control of 
neurocardiogenic syncope, the patients may lead a normal life. A need 
remains, therefore, for effective methods of treating neurocardiogenic 
syncope. The present invention is directed to meeting this need. 
SUMMARY OF THE INVENTION 
The present invention relates to methods for treating neurocardiogenic 
syncope. 
In one aspect of the present invention, the method includes administering 
to the patient an effective amount of a benzodiazepine, such as the 
benzodiazepine having the formula: 
##STR2## 
wherein R.sub.1, R.sub.2 and R.sub.5 are each selected from the group 
consisting of hydrogen and lower alkyl; and R.sub.3 and R.sub.4 are each 
selected from the group consisting of hydrogen, halogen, lower alkyl, 
nitro, amino, trifluoromethyl, and lower acylamino; at least one of 
R.sub.3 and R.sub.4 being a nitrogen containing group, 
or a pharmaceutically acceptable salt thereof. 
In another aspect of the present invention, the method includes 
administering to an adult patient from about 0.5 mg to about 1.5 mg per 
day of a benzodiazepine, such as the benzodiazepine having the formula: 
##STR3## 
wherein R.sub.3 is halogen and R.sub.4 is selected from the group 
consisting of halogen, nitro, and trifluoromethyl 
or a pharmaceutically acceptable salt thereof. 
In a further aspect of the present invention, the method includes 
administering to a patient selected from the group consisting of an infant 
and a child from about 0.01 mg/kg to about 0.05 mg/kg of the patient's 
body weight per day of a benzodiazepine, such as the benzodiazepine having 
the formula: 
##STR4## 
wherein R.sub.3 is halogen and R.sub.4 is selected from the group 
consisting of halogen, nitro, and trifluoromethyl 
or a pharmaceutically acceptable salt thereof. 
Employing the methods of the present invention, neurocardiogenic syncope in 
a patient can be treated. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention relates to methods for treating neurocardiogenic 
syncope. 
In one aspect of the present invention, the method includes administering 
to a patient a benzodiazepine, such as the benzodiazepine having the 
formula (Formula I): 
##STR5## 
in an effective amount. These compounds are benzodiazepines, which are a 
class of heterocyclic six-membered ring compounds transformed into 
hetero-ring compounds with a seven-membered ring. 
R.sub.1, R.sub.2, and R.sub.5 are each selected from the group consisting 
of hydrogen and lower alkyl. Lower alkyls include C1 to C6 alkyls, 
including linear, branched, and cyclic C1 to C6 alkyls, such as methyl, 
ethyl, n-propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 
tertbutyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl 
1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, 
n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 
1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 
1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 
2-ethylbutyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl. When 
R.sub.1, R.sub.2 or R.sub.5 are a C1 to C6 alkyl, preferably contain from 
1 to 4 carbon atoms. 
R.sub.3 and R.sub.4 are each selected from the group consisting of 
hydrogen, halogen, lower alkyl, nitro, amino, trifluoromethyl, and lower 
acylamino, with at least one of R.sub.3 and R.sub.4 being a nitrogen 
containing group. Halogen includes all four halogens, i.e., chlorine, 
bromine, iodine, and fluorine. The lower alkyls are as described above. 
The lower acylamino groups represented by R.sub.3 or R.sub.4 are those in 
which the acyl radicals are derived from lower fatty (alkanoic) acids, 
forming groups such as acetylamino, propionylamino and the like. 
Particularly preferred compounds for use in the practice of the present 
invention are those where R.sub.1, R.sub.2 and R.sub.5 are each hydrogen, 
R.sub.4 is nitro, and R.sub.3 is halogen such as chlorine, or those where 
R.sub.1, R.sub.2 and R.sub.5 are each hydrogen, R.sub.s is halogen, nitro, 
or trifluoromethyl, and R.sub.3 is halogen such as fluorine or chlorine. 
Most preferably, R.sub.1, R.sub.2 and R.sub.5 are each hydrogen, R.sub.4 
is nitro, and R.sub.3 is chlorine forming the compound known as 
clonazepam: 
5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. 
In another aspect of the present invention, the method includes 
administering to an adult patient from about 0.5 mg to about 1.5 mg per 
day of a benzodiazepine, such as the benzodiazepine having the formula 
(Formula II): 
##STR6## 
wherein R.sub.3 is halogen and R.sub.4 is selected from the group 
consisting of halogen, nitro, and trifluoromethyl 
or a pharmaceutically acceptable salt thereof. Preferably, R.sub.3 is 
chlorine and R.sub.4 is nitro, forming the compound known as clonazepam. 
The compound is preferably administered in an amount from about 0.5 mg to 
about 1.0 mg per day. 
In a further aspect of the present invention, the method includes 
administering to a patient selected from the group consisting of an infant 
and a child from about 0.01 mg/kg to about 0.05 mg/kg of the patient's 
body weight per day of a benzodiazepine, such as the benzodiazepine having 
the formula (Formula II): 
##STR7## 
wherein R.sub.3 is halogen and R.sub.4 is selected from the group 
consisting of halogen, nitro, and trifluoromethyl 
or a pharmaceutically acceptable salt thereof. Preferably, R.sub.3 is 
chlorine and R.sub.4 is nitro, forming the compound known as clonazepam. 
The compound is preferably administered in an amount from about 0.01 mg/kg 
to about 0.03 mg/kg of the patient's body weight per day. 
The following is a list of benzodiazepines which can be administered 
according to the subject invention. The list is merely illustrative and is 
not intended to be comprehensive: 
alpidem 
alprazolam 
7-aminoclonazepam 
7-aminoflunitrazepam 
7-aminonitrazepam 
bretazenil 
bromazepam 
chlordiazepoxide 
clonazepam 
demoxepam 
desalkylflurazepam 
desalkyl-3-hydroxy-flurazepam 
desmethylchlordiazepoxide 
diazepam 
estazolam 
fludiazepam 
flunitrazepam 
flurazepam 
halazepam 
4-hydroxyalprazolam 
alpha-hydroxyalprazolam 
hydroxyethylflurazepam 
3-hydroxyprazepam 
4-hydroxytriazolam 
alpha-hydroxytriazolam 
lorazepam 
medazepam 
midazolam 
nitrazepam 
norflunitrazepam 
oxazepam 
prazepam 
quazepam 
temazepam 
triazolam 
zolpidem 
The above described compounds can exist in stereochemically isomeric forms, 
that is, optical isomers and geometric isomers. Compounds suitable for 
administration in accordance with this invention include pure optical and 
geometric isomers or mixtures of these optical and geometric isomers. If 
desired, the isolation or the production of a particular stereochemical 
form can be accomplished by application of the general principles known in 
the prior art. 
The method of the present invention may also be practiced using 
acid-addition salts, preferably pharmaceutically acceptable acid-addition 
salts, of the compounds of Formula I or II, either in addition to or in 
place of the compounds of Formula I or II. The acid-addition salt forms of 
these compounds are structurally the same as the compounds of Formula I or 
II, except that the cation (generally the proton) of the acid used in 
their preparation is bonded to the nitrogen, imparting a positive charge 
thereto, and that the anion of the acid used is present to balance the 
charge. 
These acid-addition salts are prepared from any organic acid; inorganic 
acid, including organic acids having an inorganic group therein; 
organo-metallic acid, as exemplified by organic mono- and poly-carboxylic 
acids, such as those found, for example, in Beilstein's Organische 
Chemie,4th ed., Volumes III, IV, IX, X, XIV, XVII, XIX, XXI, XXII, and 
XXV, which are hereby incorporated by reference; organic mono- or 
poly-sulfonic acids or sulfinic acids, such as those found, for example, 
in Beilstein's Organische Chemie,4th ed., Volumes VI, XI, XVI, and XXII, 
which are hereby incorporated by reference; organic phosphonic or 
phosphinic acids, such as those found, for example, in Beilstein's 
Organische Chemie,4th ed., Volume XVI, which is hereby incorporated by 
reference; organic heterocyclic carboxylic, sulfonic, or sulfinic acids, 
such as those found, for example, in Beilstein's Organische Chemie,4th 
ed., Volumes XVIII, XXII, and XXV, which are hereby incorporated by 
reference; acidic ion-exchange resins; or inorganic acids of any acid 
forming element or combination of elements such as those described in 
Mellor, Comprehensive Treatise on Inorganic and Theoretical Chemistry, 
Volumes I-XVI, New York: Longman's, Green and Co., which are hereby 
incorporated by reference. In addition, other salt-forming compounds which 
are acidic in their chemical properties but which are not generally 
considered as acids in the same sense as carboxylic or sulfonic acids can 
be used to prepare the acid-addition salt forms of the compounds useful in 
practicing this invention. Thus, there are also included acidic phenolic 
compounds, such as those found, for example, in Volume VI of Beilstein's 
Organische Chemie,4th ed., which is hereby incorporated by reference, and 
acidic compounds having "activated" or acidic hydrogen atoms, such as 
those found, for example, in Cox et al.,Medicinal Chemistry , Vol. IV, New 
York: John Wiley and Sons, Inc. (1959), which is hereby incorporated by 
reference. 
Representative acids for the formation of the acid-addition salts include 
formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, 
trifluoroacetic acid, maleic acid, fumaric acid, succinic acid, succinamic 
acid, glutamic acid, tartaric acid, oxalic acid, pyromucic acid, citric 
acid, lactic acid, glycolic acid, gluconic acid, saccharic acid, ascorbic 
acid, penicillin, benzoic acid, phthalic acid, salicyclic acid, 
3,5-dinitrobenzoic acid, anthranilic acid, cholic acid, 
2-pyridinecarboxylic acid, pamoic acid, 3-hydroxy-2-naphthoic acid, quinic 
acid, tropic acid, 3-indoleacetic acid, barbituric acid, sulfamic acid, 
methanesulfonic acid, ethanesulfonic acid, isethionic acid, 
benzenesulfonic acid, p-toluenesulfonic acid, butylarsonic acid, 
methanephosphonic acid, acidic resins, hydrofluoric acid, hydrochloric 
acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, 
sulfuric acid, phosphoric acid, and the like. The acid-addition salts with 
lactic acid and with ethanesulfonic acid, for example, are water-soluble 
and are especially suitable forms for practicing the present invention. 
The acid-addition salts are prepared in conventional fashion, for instance, 
by direct mixing of the acid and the free base of the compounds having the 
structure of Formula I or II or their isoelectric forms. When this is not 
appropriate, acid-addition salt preparation can be effected by dissolving 
either or both the acid and the free base or isoelectric form separately 
in water or in an organic solvent and mixing the two solutions or by 
dissolving both the acid and the free base or isoelectric form together in 
a solvent. The resulting acid-addition salt is isolated by filtration, if 
it is insoluble in the reaction medium, or by evaporation of the reaction 
medium to leave the acid-addition salt as a residue. The acid moieties or 
anions in the salt forms of the compounds of Formula I or II are not 
critical and, therefore, can be any acid anion or acid-like substance 
capable of salt formation with the free base or isoelectric forms of these 
compounds. 
The method of the present invention can be used to treat neurocardiogenic 
syncope in a patient. 
As used herein, neurocardiogenic syncope refers to the clinical syndromes 
of syncope that result from inappropriate, and often excessive, autonomic 
reflex activity, and manifest as abnormalities in the control of vascular 
tone and heart rate. These include carotid sinus syndrome, vasovagal 
syncope, and the syndromes of cough, deglutition, and micturition syncope. 
Syncope refers to the sudden transient loss of consciousness (fainting) 
associated with the inability to maintain postural tone. Pre-syncope 
refers to premonitory signs and symptoms of imminent syncope. 
Patient, as used herein, is generally meant to be a human. An infant or 
child patient generally refers to a patient up to 10 years of age or 30 kg 
of body weight. 
Treatment, in accordance with the present invention, includes administering 
to the patient an effective amount of a compound according to Formula I or 
II or a pharmaceutically acceptable salt thereof. 
It will be appreciated that the actual preferred effective amount of 
compound will vary according to the particular compound, the particular 
composition formulated, and the mode of administration. Many factors that 
modify the compound's activity will be taken into account by those skilled 
in the art; e.g., body weight, sex, diet, time of administration, route of 
administration, rate of excretion, condition of the patient, drug 
combinations, and reaction sensitivities and severities. Administration 
can be carried out continuously or periodically within the maximum 
tolerated dose. 
Preferably, the compound is administered in an amount from about 0.5 mg to 
about 1.5 mg per day, more preferably, in an amount from about 0.5 mg to 
about 1.0 mg per day. For an infant or child patient, the compound is 
preferably administered in an amount from about 0.01 mg/kg to about 0.05 
mg/kg of the patient's body weight per day, more preferably, in an amount 
from about 0.01 mg/kg to about 0.03 mg/kg of the patient's body weight per 
day. The optimal daily dose for a particular patient can be determined by 
challenging the patient during a head up tilt test. The optimal daily dose 
of compound is the minimal dose at which the patient does not experience 
the symptoms of syncope during the head up tilt test challenge. 
The amount can be administered in a single daily dose or in multiple doses 
or even continuously. Continuous administration can be carried out in the 
inpatient setting by, for example, intravenous drip, or in an outpatient 
setting by providing the compound in a slow-release formulation, such as 
in a suspension or in microcapsules. 
Optimal administration amounts and rates for a given patient under a given 
set of conditions can be ascertained by those skilled in the art using 
conventional dosage administration tests in view of the above guidelines. 
The compound can be administered by any of the conventional modes of drug 
administration, including oral or parenteral administration. Examples of 
parenteral administration are intraventricular, intracerebral, 
intramuscular, intravenous, intraperitoneal, rectal, and subcutaneous 
administration. 
The compounds of the present invention may be administered alone or in 
combination with suitable pharmaceutical carriers or diluents. The diluent 
or carrier ingredients should be selected so that they do not diminish the 
therapeutic effects of the compounds. 
Suitable dosage forms for oral use include tablets, dispersible powders, 
granules, capsules, suspensions, syrups, and elixirs. Inert diluents and 
carriers for tablets include, for example, calcium carbonate, sodium 
carbonate, lactose, and talc. Tablets may also contain granulating and 
disintegrating agents, such as starch and alginic acid; binding agents, 
such as starch, gelatin, and acacia; and lubricating agents, such as 
magnesium stearate, stearic acid, and talc. Tablets may be uncoated or may 
be coated by known techniques to delay disintegration and absorption. 
Inert diluents and carriers which may be used in capsules include, for 
example, calcium carbonate, calcium phosphate, and kaolin. Suspensions, 
syrups, and elixirs may contain conventional excipients, such as methyl 
cellulose, tragacanth, sodium alginate; wetting agents, such as lecithin 
and polyoxyethylene stearate; and preservatives, such as 
ethyl-p-hydroxybenzoate. 
Dosage forms suitable for parenteral administration include solutions, 
suspensions, dispersions, emulsions, microcapsules and the like. They may 
also be manufactured in the form of sterile solid compositions which can 
be dissolved or suspended in sterile injectable medium immediately before 
use. They may contain suspending or dispersing agents known in the art. 
Where microcapsules are employed, they can be readily prepared by 
conventional microencapsulation techniques, such as those disclosed in, 
for example, Encyclopedia of Chemical Technology, 3rd edition, volume 15 , 
New York:John Wiley and Sons, pp. 470-493 (1981), which is hereby 
incorporated by reference. 
The benzodiazepine compounds employed in the practice of the present 
invention can be prepared by any suitable method. One method is described 
in U.S. Pat. No. 3,203,990 to Keller et al., which is hereby incorporated 
by reference. Briefly, these compounds are derived from substituted 
2-aminobenzophenones. Several synthetic routes can be employed. 
According to one method, a substituted 2-aminobenzophenone, such as 
5-nitro-2-aminobenzophenone, 5-nitro-2-methylaminobenzophenone, and the 
like is reacted with an a-amino acid or an ester thereof conforming to the 
formula (Formula III): 
##STR8## 
wherein R.sub.2 is selected from the group consisting of lower alkyl and 
hydrogen and R is selected from the group consisting of a lower alkyl and 
hydrogen. 
For example, glycine and lower alkyl glycine esters can be used. Ring 
closure occurs and a benzodiazepine conforming to Formula I above is 
obtained wherein R.sub.2 is hydrogen and R.sub.1, R.sub.3, R.sub.4 and 
R.sub.5 correspond to the substituents on the 2-aminobenzophenone used as 
starting material. The use of a longer chain .alpha.-amino acid answering 
to Formula III above wherein R.sub.2 is lower alkyl, e.g., alanine, 
results in a compound of Formula I wherein R.sub.2 is a lower alkyl group, 
i.e., a benzodiazepine containing a lower alkyl substituent in the 
3-position. 
The reaction of the 2-aminobenzophenone and .alpha.-amino acid is 
preferably effected in a solvent such as pyridine, dimethylformamide or 
the like. It is also preferable to utilize one of the materials present in 
the form of a salt of a strong organic or inorganic acid, e.g., glycine 
hydrochloride, glycine ethyl ester hydrochloride, alanine hydrochloride, 
pyridine hydrochloride, or the like. 
According to an alternate method, the substituted 2-aminobenzophenone can 
be haloacylated, such as with bromoacetyl bromide, .alpha.-bromopropionyl 
bromide, chloroacetyl chloride, or the like, to yield a 
2-(.alpha.-halo-lower alkanoylamino)-benzophenone of the formula (Formula 
IV): 
##STR9## 
wherein X is halogen; R.sub.1 and R.sub.2 are each selected from the group 
consisting of hydrogen and lower alkyl; R.sub.3, R.sub.4 and R.sub.5 are 
each selected from the group consisting of hydrogen, halogen, lower alkyl, 
nitro, amino and lower acylamino; at least one of R.sub.3, R.sub.4 and 
R.sub.5 being a nitrogen containing group. 
The resultant haloacylated-2-aminobenzophenone can then be treated with 
ammonia. This treatment with ammonia effects ring closure to obtain a 
benzodiazepine conforming to Formula I above. It is most convenient from a 
viewpoint of operating economically and ease of handling to use alcoholic 
ammonia; however, other ammonia solutions can be used as is readily 
apparent to those skilled in the art. 
Benzodiazepines conforming to Formula I above can also be prepared by 
cyclizing a 2-(.alpha.-amino-lower alkanoylamino)-benzophenone. 
The preferred compound for use in the method of the subject invention, 
clonazepam, can be prepared as specifically described in U.S. Pat. No. 
3,123,529 to Kariss and Newmark, which is hereby incorporated by 
reference. 
A stirred solution of 75 g. of 2-amino-2'- nitrobenzophenone in 700 ml. of 
hot concentrated hydrochloric acid is cooled to 0.degree. and a solution 
of 21.5 g. of sodium nitrite in 50 ml. of water is added in the course of 
3 hours. The temperature of the suspension is kept at 2-7.degree. during 
the addition. The resulting clear solution is poured into a stirred 
solution of 37 g. of cuprous chloride in 350 ml. of hydrochloric acid 1:1. 
The solid which has formed after a few minutes is filtered off, washed 
with water and recrystallized from ethanol. Crystals of 
2-chloro-2'-nitrobenzophenone melting at 76-79.degree. are obtained. 
A solution of 20 g. of 2-chloro-2'-nitrobenzophenone in 450 ml. of ethanol 
is hydrogenated at normal pressure and room temperature with Raney nickel. 
After uptake of about 6 liters of hydrogen, the catalyst is filtered off, 
and the alcohol is then removed in vacuo. The residue is distilled in a 
bulb tube at 0.4 mm. and a bath temperature of 150-165.degree. giving a 
yellow oil. The oil is dissolved in alcohol, and on addition of water, 
needles of 2-amino-2'-chlorobenzophenone melting at 58-60.degree. are 
obtained. 
To a solution of 42 g. of 2-amino-2'-chlorobenzophenone in 500 ml. of 
benzene, 19 ml. of bromoacetyl bromide is added dropwise. After refluxing 
for 2 hours, the solution is cooled, washed with 2 N sodium hydroxide and 
evaporated. The residue is recrystallized from methanol giving crystals of 
2-bromo-2'(2-chlorobenzoyl) cetanilide melting at 119-121.degree.. 
To a solution of 14.5 g. of(2-bromo-2'-(2-chlorobenzoyl) acetanilide in 100 
ml. of tetrahydrofuran, an excess of liquid ammonia (about 150 ml.) is 
added. The ammonia is kept refluxing with a Dry-Ice condenser for 3 hours 
after which time the ammonia is allowed to evaporate and the solution is 
poured into water. Crystals of 2-amino-2'-(2-chlorobenzoyl) acetanilide 
are collected, which after recrystallization from ethanol melt at 
162-164.degree.. 
A solution of 3 g. of 2-amino-2'-(2-chlorobenzoyl) acetanilide in 50 ml. of 
pyridine is refluxed for 24 hours after which time the pyridine is removed 
in vacuo. The residue is recrystallized from methanol and a mixture of 
dichloromethane and ether giving crystals of 
5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one melting at 
212-213.degree.. 
To a solution of 13.5 g. of 
5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one in 60 ml. of 
concentrated sulfuric acid, a solution of 5.5 g. of potassium nitrate in 
20 ml. concentrated sulfuric acid is added dropwise. The solution is then 
heated in a bath at 45-50.degree. for 2 1/2 hours, cooled and poured on 
ice. After neutralizing with ammonia, the formed precipitate is filtered 
off and boiled with ethanol. A small amount of white insoluble material is 
then filtered off. The alcoholic solution on concentration yields crystals 
of 7-nitro-5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one (clonazepam) 
which, after recrystallization from dichloromethane, melt at 
238-240.degree.. 
Further descriptions of the preparation of benzodiazepines such as 
clonazepam are provided in Sternbach et al. 1963 and U.S. Pat. Nos. 
3,116,203 to Kariss and Newmark, 3,121,114 to Keller et al., 3,335,181 to 
Focella and Rachlin, 4,772,599 to Watjen, 5,302,715 to Buechler and Noar, 
and 5,317,018 to Walser et al., the contents of each of which are 
incorporated by reference.

The present invention is further illustrated by the following examples. 
EXAMPLES 
Example 1 --Subjects 
Twenty-two (22) human patients with recurrent severely symptomatic 
refractory neurocardiogenic syncope (NCS)/pre-syncope were selected. 
Diagnosis of NCS was established by history, physical examination, 
exclusion of other etiologies for syncope, and positive head up tilt study 
with reproduction of symptoms. 
Patient characteristics were as follows: 
______________________________________ 
Age (years) 52.5 .+-. 22.4 
Males 12 (54.5%) 
Organic Heart Disease 
a. Hypertension 9 (40.9%) 
b. CAD 8 (36.3%) 
c. Cardiomyapathy 3 (13.6%) 
d. Impaired LVSF 4 (18.1%) 
e. MVP 2 (9.0%) 
f. SSS 6 (27.2%) 
Associated sleep 8 (36.3%) 
disorders 
Number of drugs failed 
2.1 .+-. 1.0 
Chronic fatigue 3 (13.6%) 
syndrome 
Concomitant Beta blockers 
9 (40.9%) 
______________________________________ 
LVSF=Left ventricular systolic function. 
MVP=Mitral valve prolapse. 
SSS=Sick sinus syndrome. 
Prior to clonazepam initiation, subject medication and therapeutic 
modalities included (unless contraindicated) beta blockers, high salt 
diet, Florinef, elastic stockings, Disopyramide, and/or pacemaker. 
Response to therapy was considered ineffective if symptoms recurred, 
intolerance to therapy occurred, and/or the head up tilt test (HUT) 
reproduced significant clinical symptoms in less than 30 minutes at 
70.degree. tilt. All patients had normal liver function studies and 
electroencephalogram as well as abnormal HUT. 
Example 2 - Treatment of subjects with clonazepam 
The 22 patients with recurrent severely symptomatic refractory 
NCS/pre-syncope were given clonazepam at 0.5-1.0 mg dose (in the form of 
commercially available KLONOPIN.RTM. tablets marketed by Roche 
Laboratories, Nutley, N.J. ). Nine of the 22 patients continued beta 
blocker regimens (Lopressor 25-50 mg bid or its equivalent) because of 
hypertension, arrhythmia, or coronary artery disease. 
Clonazepam treatment began at 0.5 mg dose. Early phase follow up (FU) at 
1-2 weeks included a clinic visit with clonazepam dose titration at 
0.25-0.5 mg increments according to symptom recurrence and significantly 
positive HUT. Late FU at 2-4 months included clinic visit and HUT even if 
asymptomatic to ensure absence of tachyphylaxis. If clonazepam failed at 
any level, other drugs (mainly beta blocker at a small dose) and/or other 
intervention were added at the discretion of the treating cardiologist. 
Clonazepam was discontinued if significant side effects developed or if 
the patient withdrew from the study. 
Example 3 - Results of treatment 
Twenty-two (22) patients with a follow-up of 5.9 .+-.5.5 months at a dose 
of 0.73 .+-.0.23 mg were followed. Range of follow-up was 0.5-24 months. 
At early follow up, symptom control occurred in 21 patients with symptoms 
reduced in one patient. Three of the 21 patients did not have the early 
phase HUT. In two of the 21 patients, the drug was discontinued within two 
weeks of therapy because of side effects (psychosis in one patient and 
behavioral changes in one patient). The one of the 22 patients had 
symptoms controlled. Follow up HUT was positive. Beta blocker was added to 
the therapy which lead to symptom control. The patient always continued to 
have positive HUT. At 5 months follow up, the patient developed transient 
ischemic attacks and the neurologist discontinued beta blockers and 
clonazepam. The patient was lost for follow since then. Sixteen of the 21 
patients had early phase HUT. Fifteen of the 16 patients had negative HUT 
following treatment. In one of the 15 patients the medication was 
discontinued because of side effects (dry mouth and weakness). The other 
one of the 16 patients had positive HUT and beta blocker was added and had 
complete control over symptoms. Chronic phase follow up HUT is pending for 
this patient. Eleven of the 14 patients remaining on treatment with 
negative HUT after treatment were followed for greater than 2-4 months. 
They all were asymptomatic. HUT at 2-4 months follow up was negative in 
these 11 patients. Subsequently two of the 14 patients discontinued the 
clonazepam, one due to side effects (headache) and the other withdrew from 
the study (no side effects). Twelve of the 14 patients continued without 
symptoms and tolerated the medication well. 
To summarize these results, of the 14 patients (8 males, 6 females, age 
18-84 years) who were followed for 6 weeks to 10 months, all had initial 
improvement of symptoms of NCS following initial treatment at 0.5 mg 
clonazepam. One patient withdrew from the study. At early follow up phase, 
12 of the 14 patients had negative HUT. Four of 8 required increasing the 
dose of clonazepam to 1.0 mg because of recurrence of mild symptoms. At 
0.5-1.0 mg, seven of 8 patients had no significant neurocardiogenic 
symptoms. Three of eight patients failed HUT however. The six remaining 
patients had not reached the four month follow up. 
Side effects included early sedation in 20 patients (90.9%) which persisted 
in two patients (9.1%); dry mouth in one patient (4.5%), headache in two 
patients (9.1%), psychosis in one patient (4.5%), imbalance in one patient 
(4.5%), behavioral changes in two patients (9.1%), which subsided with 
decrease in dose in one patient, and nausea in one patient (4.5%). Side 
effects required discontinuation of treatment in four patients (18.1%). 
Clonazepam thus is a centrally acting medication at a small dose (0.5 to 
1.5 mg) and is well tolerated, and is clinically effective in the 
treatment of symptomatic and refractory neurocardiogenic syncope. No 
significant development of tolerance to clonazepam on chronic follow up 
occurred. The very small daily doses of clonazepam necessary for effective 
treatment should provide a safer side effect profile than the side effect 
profiles seen with traditionally prescribed medicines for chronic 
neurocardiogenic syncope. Such traditional treatments include beta 
blockers, the hormone florinef, and anti-arrhythmic drugs. Side effects 
from beta blockers may include weakness, slowed heart rate, impotence, low 
blood pressure, and depression. Side effects with florinef include high 
blood pressure, headache, visual problems, swelling of the extremities and 
potassium deficiencies. Patients on anti-arrhythmic drugs may suffer from 
severe dry mouth and abnormal heart rhythms and, in some cases, such drugs 
can lead to congestive heart failure and/or sudden death. In contrast, the 
most common side effects of clonazepam include drug dependence, behavior 
change, sleepiness and headache; effects that are seen infrequently when 
the drug is prescribed in the small doses used to treat neurocardiogenic 
syncope. 
Although the invention has been described in detail for the purpose of 
illustration, it is understood that such detail is solely for that 
purpose, and variations can be made therein by those skilled in the art 
without departing from the spirit and scope of the invention which is 
defined by the following claims. 
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