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Патент USA US3073751

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United States Patent '
3,673,741
Patented Jan. 15, 1953
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3,075,741.
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ANTITUSSIVE COMP'OSITIDN
Alberto Vecchi and Giulio Maiiii, Milan, Italy, ‘assignors
,
to Lep‘etit S.p.A., Milan, Italy
_
No Drawing. Filed July 1, 1959, Ser. No. 824,183
6 Claims. (Cl. >167-'-55)
‘
The ‘present invention relates to new'ant‘itussive agent.
More particularly, the compound with which the in‘
ven'tion is concerned is selected from the class consisting 10
' of N,N-dimethyl-Z-phenyLZ-benzoyloxymethylbutylamine
_ For therapeutical purposes, N,N-dimethl-2-phenyl-2
O
.
benzoyloxymethylbutylamine and its mineral acid salts
may be used as such as associated with a carrier, which
15 may be a solid material, a sterile parenteral liquid or a
syrup. When the oral administration is selected as coni
ll
7
OC
a.
_
CH3
/
monly used for this type of'drugs the therapeutic ad
ministration may be providedin the form of powders,
capsules, tablets or other solid dosage forms. For paren
20 teral use, liquid diluents may be employed, such as sterile
011301120 CHQN
\ .
CH3,
distilled water, in which the mineral acid salts are freely
soluble. Although clinically appreciable effects are ob
served with doses as low as l~10 mg, the unit dosage
and its non-toxic mineral acid ‘addition salts.
is usually somewhat higher, and may safely reach 500
The compound of the invention, which for therapeutic
purposes is best used in the form of the hydrochloride,
owing to its mechanism of action, is to be classi?ed
among the centrally acting antitussive agents, as it has
been shown by pharmacological tests. Moreover, it lacks
mg. and more in stubborn cases.
any narcotic action, thus proving in this respect superior
to many natural or synthetic drugs commonly employed
in the management of coughing.
The search for central acting, non-narcotic antitu‘ssive
may be directly ?lled into capsules, either alone 01' asso
ciated with solid inert diluents and/or other active'in
Preferably the doses
are maintained under 50 mg, owing to the great e?iec
tiveness of the compound. For preparing the actual
therapeutic composition, the selected dose of the drug
gradients. Tablets may be prepared by associating the
drug with the commonly used tableting materials, such
as lactose, talc, cornstarch, stearic acid, magnesium stea
substances has been fairly intense in recent years, and has
rate or the like. Ampoules are prepared by dissolving
brought about the use of some therapeutic agents which
are capable of increasing the threshold of the medullary 35 the drug, in the form of its mineral acid salts, in sterile
distilled water. The composition may also advanta
cough center to afferent tussive impulses without the
geously take the form of a syrup, whereby the drug is dis
undesirable effects of narcotics. It has now been found
solved in the common syrup in a concentration calculated
that N,N-dimethyl-Z-phenyl - 2 - benzoyloxymethylbutyl
so as to administer the proper dose, with or without the
amine displays an antitussive effect which is favorably
comparable with that of codeine and narcotine, and is 40 ‘addition of suspending and/or ?avoring agents and/or
free from the well known side e?ects of these generally
other drugs.
employed drugs.
N,N-dimethyl-Z - phenyl - 2 - benzoyloxymethylbutyl
amine may be prepared starting from a-carbethoxy-a
The following table gives the average protecting dose,
phenylbutyric acid through the corresponding chloride,
in mg./kg., ‘of the compound of the invention against
cough caused by the inhalation of acrolein in the form 45 which in turn is converted to the dimethylamide by reac
tion with dimethylamine in an inert anhydrous organic
of aerosol in guinea pigs, by stimulation of the laryngeal
solvent. By hydrogenation with lithium aluminum hy
nerve in cats and by inhalation of sulfuric acid in dogs.
The data are compared with those obtained with codeine
and narcotine under similar conditions.
dride
50
PD“) in mg./kg. against cough
elicited by
aeroleln
inhalation
nerve in
pigs (subcu- venously)
taneously)
inhalation
in dogs
55
(intra
venously)
'
excess thionyl chloride is removed in vacuo and the res
idue is distilled collecting at l04~l06° C. under 1 mm.
-
3. 5
0. 5
1. 0
5. 0
2. O
l. 0
2. 0
20. 0
2. 0
60
Hg. Yield: 30 g. (87%) ot-carbethox‘-a-phenylbutyryl
chloride. M.P. 35-40" C.
The ‘above acyl chloride is mixed with 100‘ ml. of a
17.5% solution of dimethylamine in benzene. After 15
minutes the solution is treated with water, made acidic
The acute toxicity of the compound of the invention
is also very favorable, as is shown by the following com
parative table.
Example 1
A mixture of 32 g. u-carbethoxy-a-phenylbutyric acid
and 25 ml. thionyl chloride is re?uxed for 2 hours. The
N,N-Dlmethyl-2'phenyl-2
benzoyloxymethylbutylamine
hydrochloride
ride in anhydrous pyridine ‘gives the compound of the
invention.
The following examples are illustrative of the inven
tion.
laryngeal sulfuric acid
in guinea cats (intra-
N,N - dimethyl - 2 - phenyl-2-hydroxymethylbutyl
amine is obtained which on treatment with benzoyl chlo
65
with hydrochloric acid and extracted with ethyl ether.
3,073,741
3
The organic layer is separated and evaporated to dry
The mixture is tabletted to one hundred tablets ready
for therapeutic use.
ness. The residual crude product is recrystallized from
ligroin. Yield: 28 g. (90%) N,N-dimethyl-u-pheny1-a
Example 4
A syrup is prepared from the following ingredients:
carbethoxymethylbutyramide.
Into a mixture of 17.4 g. lithium aluminium hydride
in 150 ml. anhydrous ethyl ether a solution of 15 g. ZN,N
G.
dimethyl-a-phenyl-a-carbethoxymethylbutyramide in 90
ml. anhydrous ethyl ether is gradually dropped without
exceeding 25-27“ C. The mixture is then re?uxed for
1.5 hours and poured cautiously after cooling into 2
N,N-dimethyl-2-phenyl - 2 - benzoyloxymethylbu
tylamine hydrochloride ____________________ __
Calcium lactate
___
1.0
0.4
Phosphoric acid ____________________________ .._ 0.09
Syrup of lemon, to 100 m1.
It contains about 0.05 g. of the drug in 5 ml.
in vacuo. The residual oil (9 g., yield 76%) is N,N
We claim:
dimethyl-Z-phenyl-Z-hydroxymethylbutylamine. The hy
1. An antitussive composition in dosage unit form,
drochloride melts at 116—118° C.
15 which comprises from 0.01 to 0.5 gram of N,N-dimethyl
To a susepnsion of 7.9 g. of the amine in 35 ml. an
2-phenyl-2-benz0yloxymethylbutylamine together with a
hydrous pyridine 8.5 g. benzoyl chloride are gradually
diluent.
‘added in about 15 minutes below 15° C. After stirring
2. An antitussive composition in dosage unit form,
'for 1 hour at room temperature the mixture is poured
which comprises from ‘0.01 to 0.5 gram of I‘LN-dimethyl
into 2 volumes of water. The pH is adjusted to 8.5 and 20 2-phenyl-2-benzoyloxymethylbutylamine per dosage unit
the mixture is extracted with ethyl ether. The solvent
and a solid pharmaceutical carrier.
and the traces of pyridine are carefully removed, then
3. An antitussive composition in dosage unit form,
the residual oil is dissolved in ethyl ether and diluted
which comprises from 0.01 to 0.5 gram of N,N-dimethyl
with an ethyl ether solution of hydrogen chloride. The
2-phenyl - 2 - benzoyloxymethylbutylamine hydrochloride
precipitated crystals are collected and recrystallised from 25 per dosage unit and a liquid diluent.
ethyl acetate. Yield: 12 g. (90%) of N,N-dimethyl-2
4. An antitussive composition as in claim 3, wherein
phenyl-Z-benzoyloxymethylbutylamine, M.P. 17l—173° C.
the liquid diluent is sterile distilled water.
The free base may be obtained in a pure grade by dis
5. An antitussive composition in syrup form, which
solving the hydrochloride in water, making the solution
comprises from 0.1 to 1.0 percent of N,N-dimethyl-2
volumes of cold water.
The mixture is extracted with
ethyl ether and the organic layer is evaporated to dryness
alkaline, extracting with ethyl ether and evaporating 30 phenyl-Z-benzoyloxymethylbutylamine hydrochloride, to
the extract to dryness.
gether with a syrupy pharmaceutical carrier.
6. An antitussive composition containing in a dosage
Example 2
unit form from 0.01 to 0.5 gram of a member of the
group consisting of N,N-dimethyl-2-phenyl»2-benzoyloxy
Three grams of N,N-dimethy1-2-phenyl-2-benzoyloxy
methylbutylamine are ?lled into one hundred capsules and 35 methylbutylamine and its non-toxic mineral acid salts,
together with a diluent.
are ready for therapeutic use.
Example 3
The following ingredients are thoroughly admixed:
N,N-dimethyl~2-phenyl - 2 - benzoyloxymethylbutyl
amine hydrochloride ______________________ __
Cornstarch
Talc
Stearic acid ________________________________ __
40
References Cited in the ?le of this patent
UNITED STATES PATENTS
G.
81,446
1,794,292
5.0
2,421,129
2,486,375
15.0
2.5
0.5
Whitlow ____________ __ Aug. 25,
H0110 ______________ __ Feb. 24,
Reasenberg _________ ___ May 27,
Cope _______________ __ Nov. 1,
1868
1931
1947
1949
FOREIGN PATENTS
17,085
Great Britain _______________ __ 1914
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