Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
109~i3~
S~TMMARY AND DETAILED_DESCRIPTION
; The present invention relates to new l-piperidine-
butanol compounds and methods for their preparation. More
particularly, the invention relates to (+~-)-ciS-a-[3-(2~6-
dimethyl-l-piperidinyl)propyl]-a-phenyl-2-pyridinemethanol
which has the formula
CH
C-(CH2)3-
C6H5 I 3
'
to acid-addition salts thereof, methods for the production of the
foregoing compounds, pharmaceutical compositions containing
~said compounds and methods for treating cardiac arrhythmia
using said compounds.
In accordance with the invention, the foregoing
compounds can be produced by reacting a compound of the formula
~.
N Li
II
with a compound of the formula
CH3
10 ~ ~
C6H5-C-(CH2)3-N
CH3
having a cis configuration.
--2--
~G3~3Z
This reaction is generally carried out in a solvent
such as an ether (diethyl ether, tetrahydrofuran, diethylene
glycol dimethyl ether, etc.), a hydrocarbon (benzene, toluene,
hexane, heptane, etc.), or mixtures thereof for periods of -
from one to twelve hours at from -80C. to +10C., preferably
one to two hours at -60C. to -80C. followed by one to three
hours at from -5C. to +5C. The preferred solvent system
employs tetrahydrofuran, optionally mixed with heptane.
While at least one mole of pyridyllithium (II) should
be used for each mole of piperidine compound (III), an excess
of the lithium compound is preferred.
The intermediate metallic derivative of a compound
of formula I is hydrolyzed under acidic (dilute aqueous hydro-
chloric acid, aqueous ammonium chloride, dilute aqueous sulfuric
i
acid, etc ), neutral or basic (dilute aqueous sodium hydroxide,
dilute aqueous potassium hydroxide, etc.) conditions, preferably
neutral conditions.
The product may be isolated as the free base or an
acid-addition salt thereof by suitable adjustment of the pH-
The cis-r-(2,6-dimethylpiperidino)butyrophenone is
prepared by reacting an excess of cis-2,6-dimethylpiperidine
with r-chlorobutyrophenone, ethylene ketal in the presence of
sodium iodide at reflux for about forty-eight hours, followed by
hydrolysis of the resulting amino ketal with aqueous hydro-
chloric acid and then basification with aqueous sodium
hydroxide.
1~63~Z
The ~-chlorobutyrophenone, ethylene ketal is prepared
by reacting ~-chlorobutyrophenone with ethylene glycol using
p-toluenesulfonic acid as a catalyst. The reaction is carried
out utilizing benzene as a solvent and a water trap coupled
into the reaction system. The reaction mixture is refluxed
until the desired amount of water is collected, followed by
neutralization of the acid and removal of the solvent.
Also, in accordance with the invention, the compounds
of the invention can be prepared by reacting a compound of the
~formula ~ CH3
(CH2)3 Li
CH3
IV
having a _ configuration with 2-benzoylpyridine in a
suitable solvent such as an ether (diethyl ether, tetrahydro-
furan, diethylene glycol dimethyl ether, etc.) for from four
hours to twenty-four hours at 0C. to 60C. The preferred
reaction conditions employ tetrahydrofuran as the solvent and
a reaction time of from twelve hours to eighteen hours at a
temperature range of from 20C. to 35C.
It is preferred to use approximately equivalent
~!amounts of the lithium derivative of structure IV and 2-
benzoylpyridine.
1~638Z
The intermediate metallic derivative of a compound
of formula I is hydrolyzed under acidic (dilute aqueous
hydrochloric acid, aqueous ammonium chloride, dilute aqueous
sulfuric acid, etc ), neutral or basic (dilute aqueous sodium
hydroxide, dilute aqueous potassium hydroxide, etc.) conditions,
preferably neutral conditions.
The product may be isolated as the free base or an
acid-addition salt thereof by suitable adjustment of the pH.
The cis-1-(3-lithiopropyl)-2,6-dimethylpiperidine
~)is prepared by reacting one equivalent of cis-1-(3-chloropropyl)-
; 2,6-dimethylpiperidine with two equivalents of lithium over a
six-hour period in tetrahydrofuran. After filtration, the
remaining solution is reacted directly with benzophenone.
The cis-1-(3-chloropropyl)-2,6-dimethylpiperidine is
prepared bv reactin~ thionYl chloride with cis-2,6-dimethyl-
l-piperidinepropanol in benzene at a temperature of from 0C.
to 5C. for thirty minutes followed by two hours at reflux. The
chlorinated product is isolated as the hydrochloride by filtration.
The cis-2,6-dimethyl-1-piperidinepropanol is prepared
~by reacting 3-bromopropanol with an excess of cis-2,6-dimethyl-
piperidine in refluxing xylene for a period of about two hours.
The cis-2,6-dimethyl-1-piperidinepropanol is separated by
distillation.
;382
The free base of formula I forms acid-addition
salts, which are also part of this invention, with any of
variety of inorganic and organic acids. Typical acid-
-addition salts are formed with such acids as hydrochloric,
hydrobromic, sulfuric, sulfamic, nitric, phosphoric, acetic,:
citric, tartaric, succinic, oxalic, benzoic, maleic, malic,
lactic, gluconic, naphthalene-1,5-disulfonic, methane-
sulfonic, ~-toluenesulfonic, and pamoic acids. The free bases
and their salt forms are interconvertible by adjustment of the
l~pH. They differ in solubility properties but are otherwise `
equivalent for the purposes of the invention.
The compounds of the invention can exist in anhydrous
form as well as in solvated, including hydrated, forms. In
general, the hydrated forms and the solvated forms with
; pharmaceutically-acceptable solvents are equivalent to the
anhydrous or unsolvated form for the purposes of the invention.
The compounds of the inventions may also be obtained as R and
S isomers by standard resolution techniques.
The compounds of the invention are new chemical
~ al~le ~ ph~r~^loo~ ents. M~re s~e~ -
fically, these compounds are antiarrhythmic agents. The
activity of these compounds is shown by way of the following
antiarrhythmic screen
--6--
~9~,3~:
Dogs were operated on according to the procedure
reported in Circulation 1, 1318 (1950). (~ )-cis-a-~3-
(2,6-Dimethyl-l-piperidinyl)propyl]-a-phenyl-2-pyridine-
methanol, lidocaine and quinidine were tested intravenously
nineteen to twenty-four hours after coronary artery ligation
The degree of effectiveness of the compound was determined
by the degree of conversion of ventricular ectopic beats to
sinus beats. The table shown below gives the results of
the screen performed on (+,-)-c~s-a-[3-2,6-dimethyl-1-piperi-
l~dinyl)propyl]-a-phenyl-2-pyridinemethanol and the known anti-
arrhythmic agents, lidocaine and quinidine.
TABLE
Time
Compound Dose*Post Dose% Conversion
Lidocaine 10 mg/kg i.v.5 min. 92
20 min. o
55 min. o
Quinidine 20 mg/kg i.v.5 min. 66
20 min. 35
55 min. - 41
;~e,~
(+,-)-cis-a- 5 mg/kg i.v. 2 min. 91
~3-(2,6-di- 20 min. 76
methyl-l- 55 min 66
piperidinyl)-
propyl]-a-
pheny1-2-pyri-
dinemethanol
*Dose calculated as free base,tested as salts.
1~63~2'
In addition the present invention relates to
pharmaceutical compositions and methods employing (+,-)-cis-
a-[3-(2,6-dimethyl-1-piperidinyl)propyl]-a-phenyl-2-pyridine-
methanol and pharmaceutically acceptable acid-addition salts
thereof. Some typical examples of pharmaceutically acceptable
acid-addition salt forms are the hydrochloride, sulfate, phos-
phate, citrate, pamoate, acetate and maleate salts.
More particularly, (+,-)-cis-a-[3-(2,6-dimethyl-1-
piperidinyl)propyl]-a-phenyl-2-pyridinemethanol and pharma-
~,ceutically acceptable acid-addition salts thereof are highly
useful in controLing cardiac arrhythmias in mammals, such as
cats, dogs, horses, human beings, etc., when administered in
amounts ranging from about 0.1 mg. to about 10 mg. per kg. of
body weight per day, and such dosage units are employed that
a total of from about 7 mg. to about 700 mg. of active ingre-
dient for a subject of about 70 kg. body weight are administered
in a 24 hour period, preferably in divided doses. A preferred
dosage regimen employs a range of from 1 mg. to 5 mg. of active
ingredient per kg. of body weight per day and wherein the total
daily dosage is divided into four units and each taken after an
appropriate time interval.
The compounds of the present invention may be admin-
istered byany convenient route such as orally, intraperitoneally,
subcutaneously, intramuscularly or intravenously.
1~6382:
Compositions according to the present invention having
the desired clarity, stability, and adaptability for parenteral
use are obtained by dissolving from O.lOV/o to 10.0% by weight
of active compound in a vehicle such as water, a polyhydric
aliphatic alcohol or mixtures thereof. In addition to water,
especially satisfactory are glycerin, propylene glycol, and the
polyethylene glycols. The polyethylene glycols consist of a
mixture of non-volatile, normally liquid, polyethylene glycols
which are soluble in both water and organic liquids and which
~have molecular weights of from about 200 to about 1500. Although
the amount of active compound dissolved in the above vehicle may
vary from 0.10% to 20.0% by weight, it is preferred that the
amount of active compound employed be from about 1.0% to about
10.0% by weight. Although various mixtures of the aforementioned
non-volatile polyethylene glycols may be employed, it is pre-
ferred to use a mixture having an average molecular weight of
from about 200 to about 400.
In addition to the active compounds, the parenteral
solutions of the present invention may also contain various
~preservatives which may be used to prevent bacterial and fun-
gal contamination. The preservatives which may be used for
such purpose are, for example, benzyl alcohol, myristyl-gamma-
-picolinium chloride, phenyl mercuric nitrate, benzalkonium
chloride, phenethyl alcohol, p-chlorophenyl-a-glycerol ether,
methyl and propyl parabens, and thimerosal. As a practical
1~963~3Z
;
matter is is also convenient to employ antioxidants. Suitable
antioxidants include, for example, sodium bisulfite, sodium
metabisulfite, and sodium formaldehyde sulfoxylate. Generally,
from about 0.05% to about 0.2% concentrations of antioxidant
are employed.
The preferred concentration of active compound is
1 to 50 mg./ml. of the finished compositions when intramuscular
injection is the purpose for which the compositions are in-
tended. They are equally adapted to intravenous administration
Owhen diluted with water or diluents employed in intravenous
therapy such as isotonic glucose in appropriate quantities. For
this use, ini,ial concentrations down to about .5 to 25 mg./ml.
of active compound are satisfactory. They are also adapted to
oral administration when diluted with drinking water.
The active compounds of the present invention may be
orally administered, for example, with an inert diluent or with
an assimilable edible carrier, or they may be enclosed in hard
or soft gelatin capsules, or they may be compressed into tablets,
or they may be incorporated directly with the food of the diet.
For oral therapeutic administration, the active compounds of
this invention may be incorporated with excipients and used
in the form of tablets, troches, capsules, elixirs, suspensions
syrups, wafers, chewing gum, and the like. Such compositions
and preparations should contain at least 0.1% of active com-
pound. The percentage in the compositions and preparations
may, of course, be varied and may conveniently be between about
-10-
`;
~G3~Z
5% to about 75% or more of the weight of the unit. The amount
of active compound in such therapeutically useful compositions
or preparations is such that a suitable dosage will be obtained.
Preferred compositions or preparations according to the present
invention are prepared so that an oral dosage unit form contains
between about 1 and 200 milligrams of active compound.
The tablets, troches, pills, capsules and the like
may also contain the following: a binder such as gum traga-
canth, acacia, corn starch or gelatin; an excipient such as
~dicalcium phosphate; a disintegrating agent such as corn starch,
potato starch, alginic acid and the like; a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose,
lactose or saccharin may be added or a flavoring agent such as
peppermint, oil of wintergreen, or cherry flavoring. When the
dosage unit form is a capsule, it may contain in addition to
materials of the above type a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to
otherwise modify the physical form of the dosage unit, for
instance, tablets, pills or capsules may be coated with
shellac, sugar, or both. A syrup or elixir may contain the
active compounds, sucrose as a sweetening agent, methyl and
propyl parabens as preservatives, a dye and a flavoring such
as cherry or orange flavor. Of course, any material used in
preparing any dosage unit form should be pharmaceutically pure
and substantially nontoxic in the amounts employed.
The invention is illustrated by the following examples:
-11-
1~9(~3~2
Example 1:
At -78C. 180 ml. of a 1.6M solution of butyl lithium
in heptane is added with stirring to 200 ml. of tetrahydrofuran.
The mixture is stirred under nitrogen while a solution of 43 g.
of 2-bromopyridine in 50 ml. of tetrahydrofuran is added slowly
while maintaining the temperature below -65C. After stirring
for one hour, the mixture is treated with a solution of 65 g.
of cis-~-(2,6-dimethylpiperidino)butyrophenone in 70 ml. of
tetrahydrofuran over a period of 10 minutes and stirred at
-65 to -75C. for one additional hour. The mixture is stirred
~and allowed to warm to 0C. over a period of 2 hours, then
treated with 30 ml. of water. The supernatant organic layer
is decanted from the precipitated solid and evaporated at
reduced pressure to about one-third its previous volume. The
residue is poured into 2.5 1. of cold dilute aqueous sodium
hydroxide. The resulting precipitate of (+,-)-cis-a-[3-(2,6-
dimethyl-l-piperidinyl)propyl]-a-phenyl-2-pyridinemethanol is
removed by filtration, washed with water and dried; m.p. 70-71C.
after crystallization from petroleum ether.
If the product is recrystallized from aqueous methanol,
a monohydrate results; m.p. 101-102C.
The monohydrochloride salt is prepared by dissolving
the anhydrous free base in 2-propanol and adding an equivalent
amount of a 10~ solution of dry hydrogen chloride in 2-propanol,
-12-
1~963~Z
followed by dilution with ether and filtration of the preci-
pitated salt; m.p. 171-172C.
Intermediates
a) cis-~-(2,6-Dimethylpiperidino)butyrophenone
- A mixture of 619 g. of ~-chlorobutyrophenone, ethylene
ketal, ~00 g. of cis-2,6-dimethylpiperidine and 16 g. of sodium
iodide is stirred and heated at reflux for 48 hours. The
mixture is cooled, diluted with 1 1. of anhydrous ether and
-~ filtered to remove c~s-2~6-dimetbylp;p~ridine hydrochlor-de~
The ~ilter cake is washed with 1 1. of ether and the filtrate
and washings combined. The resulting ether solution is washed
five times with 500 ml. portions of water, then extracted with
a solution of 300 ml. of concentrated hydrochloric acid in
3 1. of water. The acid extract is washed with 500 ml. of
ether, then heated to 70-80 and allowed to cool to room
temperature over a period of 16 hours. The resulting solution
is basified with 50% aqueous sodium hydroxide and the organic
layer is separated. The aqueous layer is extracted with 500 ml.
of ether and the extract is combined with the organic layer.
The combined extract is washed several times with water, dried
and evaporated. The oily residue is distilled at reduced
pressure to give cis-~-(2,6-dimethylpiperidino)butyrophenone;
b.p. 138-141 C. /Q. 1 mm.
-13-
b) ~-Chlorobutyrophenone, EthYlene Ketal
A mixture of 500 g. of ~-chlorobutyrophenone, 225 g.
of ethylene glycol, 10 g of ~-toluenesulfonic acid and 1.5 1.
of benzene is heated at reflux under a water separator until
water collection ceases. The resulting solution is cooled,
neutralized with 10 ml. of triethylamine and evaporated at
reduced pressure to give ~-chlorobutyrophenone, ethylene ketal,
suitable for use without further purification. (The pure
material boils at 100-118 C./0 1-0.8 mm. and melts at 57-59C.)
Example 2:
A soiution of 18.9 g. of cis-1-(3-chloropropyl)-2~6-
dimethylpiperidine in 50 ml. of tetrahydrofuran is added
dropwise under a nitrogen atmosphere to a stirred mixture of
1.4 g. of lithium wire and 50 ml. of tetrahydrofuran over a
period of 2 hours. After the addition is complete, the mixture
is stirred another 4 hours under nitrogen, the excess lithium
metal removed manually and a solution of 18.3 g. of 2-benzoyl-
pyridine in 100 ml. of tetrahydrofuran is added dropwise with
stirring over a period of 2 hours. The mixture is stirred
for 16 hours, then treated with 5 ml. of water. The organic
phase is decanted from the precipitated solid and evaporated
at reduced pressure to about one-fourth its previous volume.
-14-
1~39~;3~,~
This solution is poured into 400 ml. of water, the solution
is acidified with acetic acid and washed with ether. The
aqueous acid solution is basified with aqueous sodium hydroxide
and extracted with ether. The ether extract is washed with
water, dried and evaporated to give (~ cis-~-[3-(2,6-
dimethyl-l-piperidinyl)propyl]-a-phenyl-2-pyridinemethanol;
m.p. (monohydrate) 100-102C. after crystallization from
aqueous methanol.
Intermediates
'a) cis-1-(3-Chloropropyl)-2,6-dimethylpiperidine
__ _
A stirred solution of 171 g. of cis-2,6-dimethyl-1-
piperidinepropanol in 400 ml. of benzene is cooled to 0-5 and
143 g. of thionyl chloride is added dropwise over a period of
30 minutes. The mixture is then heated at reflux for 2 hours,
cooled and diluted with 1 1. of ether. The resulting preci-
pitate of cis-1-(3-chloropropyl)-2,6-dimethylpiperidine
hydrochloride is collected by filtration; m.p. 173-174C. after
crystallization from 2-propanol-ether. The free base is
prepared as needed by dissolving the hydrochloride in a minimum
~Oamount of water, cooling and adding a slight excess of 50~
aqueous sodium hydroxide. The liberated base is immediately
extracted with several portions of benzene The extracts are
combined, dried and evaporated to give the free base, cis-l-
(3-chloropropyl)-2,6-dimethylpiperidine.
-15-
~ 63~
b) cis-2,6-Dimethyl-l-piperidinepropanol
A stirreà soiution of 46G g. of cis-c,6-1li,le,hyl-
piperidine in 300 ml. of xylene is treated with 278 g. of
3-bromopropanol over a period of 15 minutes. The mixture is
stirred and heated at reflux for 2 hours, then allowed to cool
while stirring for 16 hours. The mixture is filtered and the
filtrate evaporated at reduced pressure. The residue is
distilled at reduced pressure to give cis-2,6-dimethyl-1-
- piperidinepropanol; b.p. 147-149C./25 mm.
Example 3:
Preparation of capsule formulation
; Ingredient Milligrams per Capsule
(+,-)-cis-a-[3-(2,6-dimethyl-1-
piperidinyl)propyl]-a-phenyl-
2-pyridinemethanol hydrochloride . . . . . . . . . 200
Starch . . . . . . . . . . . . . . . . . . . . . . . 80
Magnesium stearate . . . . . . . . . . . . . . . . . 5
The active ingredient, starch and magnesium stearate
are blended together. The mixture is used to fill hard shell
2~capsules of a suitable size at a fill weight of 285 milligrams
per capsule.
-16-
